Benzazole Derivatives as Histamine H4 Receptor Ligands

ABSTRACT

The present patent application concerns new ligands of the H4-receptor, their process of preparation and their therapeutic use.

This application is a divisional of application Ser. No. 13/825,989,filed May 21, 2013 (which is hereby incorporated by reference).

The present patent application concerns new ligands of the H4-receptor,their process of preparation and their therapeutic use.

Until recently, the pro-inflammatory actions of histamine were thoughtto be essentially mediated by the H1 receptor and H1 receptorantagonists have found large therapeutic applications in allergicmanifestations like the anaphylactic shock, allergic rhinitis,dermatitis, pruritus, etc.

However these drugs essentially prevent the occurrence of major symptomsof these manifestations without modifying clearly the progressivedevelopment of the inflammatory process leading to chronic diseases likeasthma in which, however, histamine release from mast-cells mightrepresent an important trigger (reviewed in Galli et al, Nature, 2008,454, 445).

The recent discovery of the histamine H4 receptor (H4R) has modifiedthis landscape (reviewed in Thurmond et al, Nature Rev. Drug Disc.,2008, 7, 41). The H4R belongs to the superfamily of G-protein coupledheptahelical receptors and is expressed on the plasma membranes of avariety of immunocompetent/inflammatory cells, e.g. eosinophils,basophils, mast-cells or dendritic cells. The H4R has a chimiotacticrole, controlling the afflux of e.g. mast-cells or eosinophils toinflammatory sites that is elicited by histamine release and, therebyplays a major role in the development of chronic inflammatory disorders.It also controls the activity of eosinophils and some classes oflymphocytes. Blockade of the H4R by antagonists or inverse agonistsshould therefore constitute a novel therapeutic approach in diseaseslike asthma, emphysema, allergic rhinitis, nasal congestion, bronchitis,chronic obstructive pulmonary disease, dermatitis, arthritis, psoriasis,colitis, etc. in which they could be used alone or in association withalready used other classes of anti-inflammatory medications, namely H1Rantagonists. In addition the utilisation of H4R antagonists/inverseagonists is also of potential interest in a variety of autoimmunediseases e.g. type I diabetes, Crohn's disease, multiple sclerosis,lupus, etc. . . . . The itch-preventing effect of some H4R antagonistsin a rodent model (Bell et al, Br J Pharmacol, 2004, 142, 374) alsosuggests the use of these agents in pruritus, a manifestation onlyimperfectly controlled by available medications, namely H1R antagonists.

H4R antagonists/inverse agonists have not yet reached clinical uses andthere is therefore a need for compounds displaying high potency andsafety. In the present application a novel chemical class of H4R ligandsis disclosed.

The instant invention thus relates to novel benzazoles derivatives as H4receptor ligands, to their preparation and to their application intherapeutics.

According to a first object, the present invention concerns newcompounds of formula (I):

wherein:

X represents NR′, S or O;

HetAr represents a phenyl or heteroaryl, optionally substituted with oneor more substituents chosen from halogen, OR″ alkyl, cyano, NR″R′″,—COR″, —COOR″, —CONR″R′″, aryl, -alkylaryl;

R represents a lower alkyl or H;

R′ represents H, lower alkyl, alkoxyalkyl or alkoxycarbonyl;

R″, R′″ identical or different independently represent H or alkyl;

HET representing a non aromatic monocyclic heterocycle containing atleast one nitrogen atom, which is linked to R;

B represents a single bond or an -alkyl- group;

A represents O, NH or S;

Ar is a mono or polycyclic aromatic or a mono or polycyclicheteroaromatic which can be optionally substituted with one or more of:

-   -   halo; azido; cyano; hydroxy; nitro;    -   alkyl; alkoxy; alkylsulfanyl; alkenyl; alkynyl; alkenyloxy;        alkenyloxy; alkenylsulfanyl; alkynylsulfanyl; cycloalkoxy;        cycloalkylalkyl;        -   whose alkyl, alkenyl, alkynyl or cycloalkyl part can be            substituted with one or more of halo, hydroxy, polyhydroxy,            alkoxy, hydroxyalkoxy, cyano, amino, aminoalkyl, alkylamino,            dialkylamino, aminoalkylamino, aminoalkylaminocarbonyl,            alkoxycarbonylamino, diarylmethylimino (where aryl is            optionally substituted with one or more of hydroxy or halo),            cycloalkenylimino (where cylalkenyl is optionally            substituted with one or more of alkyl, OH), alkylsulfanyl,            alkylsulfinyl, alkylsulfonyl, cycloalkyl, polycycloalkyl,            cycloalkenyl, polycycloalkenyl, guanidino,            alkylcarbonylguanidino, acylguanidino, cyanoguanidino,            alkoxycarbonylguanidino, alkoxycarbonyl,            alkoxycarbonylalkylamino, alkoxycarbonylalkylcycloalkyl,            alkoxycarbonylheterocyclyl, aminocarbonyl,            alkylaminocarbonyl, alkylcarbonyl, alkylcarbonylalkoxy,            aryloxy, arylsulfanyl, arylsulfinyl, arylsulfonyl,            heteroaryl, heterocyclyl (heterocyclyl being optionally            substituted with one or more of oxo, amino, imino),            heteroaryloxy, heterocyclyloxy, heteroarylamino,            heterocyclylamino, hydrazinocarbonyl,            hydroxyalkylcycloalkyl, N-alkyl(thioureido), phthalimido,            ureido, oxocycloalkenylamino substituted with amino,            carbamimidoylheterocyclyl;    -   amino; alkylamino; alkylcarbonyl; alkoxycarbonyl; alkylsulfanyl;        alkylsulfinyl; alkylsulfonyl; alkylsulfonyloxy

whose alkyl can be substituted with one or more of halo;

-   -   aminocarbonyl which can be N-substituted with one or two of        alkyl, aryl, arylalkyl;    -   aryl; arylalkyl; aryloxy; arylalkoxy; arylalkylamino;        arylalkylsulfanyl; heteroaryl; heteroaryloxy        -   whose (hetero)aryl part can be substituted with one or more            of amino, halo, alkyl, (poly)haloalkyl, hydroxyalkyl,            alkoxy, (poly)haloalkoxy, alkoxycarbonylamino,            alkylcarbonyl, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl,            nitro, cyanoalkyl, or fused with a non aromatic heterocycle;    -   heterocyclyl; heterocyclyloxy; heterocyclylalkoxy        -   whose heterocycle can be substituted with one or more of            halogenoalkyl, acylamino, acyloxy, amino, alkyl, alkylamino,            dialkylamino, aminoalkyl, oxo, carbamimidoyl, halo, hydroxy,            hydroxyalkyl, hydroxymethyl, alkoxcarbonyl;

or

-   -   fused with a non aromatic heterocycle (optionally substituted        with one or more of halogens) or carbocycle;

as well as their enantiomers, diastereomers, mixtures thereof andpharmaceutically acceptable salts, tautomers, hydrates and solvates.

Unless specified otherwise, the terms used hereabove or hereafter havethe meaning ascribed to them below:

“Halo” or “halogen” refers to fluorine, chlorine, bromine or iodineatom.

Halogenoalkyl refers to a C1-C9-alkyl moiety wherein one or morehydrogen atoms and refers in particular to perhaloalkyl.

“Perhaloalkyl” represents a C1-C9-alkyl moiety wherein all hydrogenatoms are substituted with same or different halogen atoms, for example,—CF₃, —CHF₂, —CCl₃, —CF₂Cl, —CH₂Cl, —CH₂CF₂—CF₃.

“Perhaloalkoxy” represents a perhaloalkyl linked via an oxygen atom, forexample, —O—CF₃, —O—CHF₂, —O—CH₂CF₃.

“Alkyl” represents an aliphatic-hydrocarbon group which may be straightor branched having 1 to 20 carbon atoms in the chain unless specifiedotherwise. Preferred alkyl groups have 1 to 12 carbon atoms, morepreferably have 1 to 6 carbon atoms in the chain; lower alkyls havepreferably 1 to 4 carbon atoms. Branched means that one or more loweralkyl groups such as methyl, ethyl or propyl are attached to a linearalkyl chain. Exemplary alkyl groups include methyl, ethyl, n-propyl,i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, octyl, nonyl, decyl.

“Alkenyl” refers to an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be straight or branched having 2to 15 carbon atoms in the chain unless specified otherwise. Preferredalkenyl groups have 2 to 12 carbon atoms in the chain; and morepreferably about 2 to 6 carbon atoms in the chain. Exemplary alkenylgroups include ethenyl, propenyl, n-butenyl, i-butenyl,3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, nonenyl, decenyl.

“Alkynyl” refers to an aliphatic hydrocarbon group containing acarbon-carbon triple bond and which may be straight or branched having 2to 15 carbon atoms in the chain unless specified otherwise. Preferredalkynyl groups have 2 to 12 carbon atoms in the chain; and morepreferably 2 to 4 carbon atoms in the chain. Exemplary alkynyl groupsinclude ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methyl-1-butynyl,n-pentynyl, 4,4-dimethyl-2-pentynyl, heptynyl, octynyl and decynyl.

“Carbocycle” refers to a saturated or saturated on unsaturated nonaromatic mono- or multicyclic hydrocarbon ring system of 3 to 10 carbonatoms, preferably of 4 to 10 carbon atoms.

“Cycloalkyl” refers to a saturated non-aromatic mono- or multicyclichydrocarbon ring system of 3 to 10 carbon atoms, preferably of 4 to 10carbon atoms. Preferred ring sizes of rings of the ring system include 4to 6 ring atoms. Exemplary monocyclic cycloalkyl include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.Exemplary multicyclic cycloalkyl include 1-decalin, norbornyl,adamant-(1- or 2-)yl.

“Aryl” refers to an aromatic monocyclic or multicyclic hydrocarbon ringsystem of 6 to 14 carbon atoms, preferably of 6 to 10 carbon atoms.Exemplary aryl groups include phenyl, naphthyl, indenyl, phenanthryl,biphenyl.

The terms “heterocycle” or “heterocyclic” refer to a saturated orpartially unsaturated non aromatic stable 3 to 14, preferably 5 to10-membered mono, bi or multicyclic rings wherein at least one member ofthe ring is a hetero atom. Typically, heteroatoms include, but are notlimited to, oxygen, nitrogen, sulfur, selenium, and phosphorus atoms.Preferable heteroatoms are oxygen, nitrogen and sulfur. Suitableheterocycles are also disclosed in the Handbook of Chemistry andPhysics, 76th Edition, CRC Press, Inc., 1995-1996, pages 2-25 to 2-26,the disclosure of which is hereby incorporated by reference. Preferrednon aromatic heterocyclic include, but are not limited to oxetanyl,tetrahydrofuranyl, dioxolanyl, tetrahydropyranyl, dioxanyl,pyrrolidinyl, piperidyl, morpholinyl, imidazolidinyl, pyranyl. Preferredsaturated heterocycles are chosen from tetrahydrofuranyl, dioxolanyl,tetrahydropyranyl, dioxanyl, pyrrolidinyl, piperidyl, morpholinyl,imidazolidinyl, more preferably tetrahydrofuranyl, dioxolanyl,tetrahydropyranyl.

The term “heteroaryl” refers to a 5 to 14, preferably 5 to 10 memberedaromatic mono-, bi- or multicyclic ring wherein at least one member ofthe ring is a hetero atom. Examples include pyrrolyl, pyridyl,pyrazolyl, thienyl, pyrimidinyl, pyrazinyl, tetrazolyl, indolyl,quinolinyl, purinyl, imidazolyl, thienyl, thiazolyl, benzothiazolyl,furanyl, benzofuranyl, 1,2,4-thiadiazolyl, isothiazolyl, triazoyl,tetrazolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl,carbazolyl, benzimidazolyl, isoxazolyl.

“Acyl” means an H—CO— or alkyl-CO— group wherein the alkyl group is asherein described. Preferred acyls contain a lower alkyl. Exemplary acylgroups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyland palmitoyl.

“Alkyl”, “cycloalkyl”, “alkenyl”, “alkynyl”, “aryl”, “heteroaryl”,“heterocycle” also refers to the corresponding “alkylene”,“cycloalkylene”, “alkenylene”, “alkynylene”, “arylene”, “heteroarylene”,“heterocyclene” which are formed by the removal of two hydrogen atoms.

As used herein, “carbamimidoyl” also refers to “amidino”.

A first group of compounds according to the invention may be defined asfollows:

wherein:

X represents NR′ or S;

HetAr represents a phenyl, optionally substituted with one or moresubstituents chosen from hydrogen, halogen, amino, alkyl;

R represents H or a lower alkyl;

R′ represents H, alkyl, alkoxyalkyl, alkoxycarbonyl;

HET representing a non aromatic 5 or 6 membered heterocycle containingone nitrogen atom, which is linked to R;

B represents a single bond or a —CH₂— group;

A represents O, NH or S;

Ar is a thienyl, phenyl or naphtyl or 5 to 6 membered heteroaromaticwhere the phenyl can be optionally substituted with one or more of:

-   -   halo; azido; cyano; hydroxy; nitro; alkyl;    -   alkoxy; alkylsulfanyl; alkenyl; alkenylsulfanyl; alkynyl;        alkenyloxy; alkenyloxy; cycloalkoxy; cyloalkylalkyl        -   whose alkyl, alkenyl, alkynyl or cycloalkyl part can be            substituted with one or more of halo, hydroxy, alkoxy,            hydroxyalkoxy, cyano, amino, aminoalkyl, alkylamino,            aminoalkylamino, dialkylamino, aminoalkylaminocarbonyl,            alkoxycarbonylamino, diarylmethylimino (where aryl is            optionally substituted with one or more of hydroxy or halo),            cycloalkenylimino (where cylalkenyl is optionally            substituted with one or more of alkyl, OH), alkylsulfanyl,            alkylsulfonyl, cycloalkyl, (poly)cycloalkenyl, guanidino,            alkylcarbonylguanidino, acylguanidino,            alkoxycarbonylguanidino, alkoxycarbonyl,            alkoxycarbonylalkylamino, alkoxycarbonylheterocyclyl,            aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl,            alkylcarbonylalkoxy, aryloxy, arylsulfonyl, heteroaryl,            heterocyclyl (heterocyclyl being optionally substituted with            one or more of oxo, amino, imino), heterocyclylamino,            hydrazinocarbonyl, N-alkyl(thioureido), phthalimido, ureido,            oxocycloalkenylamino substituted with amino,            carbamimidoylheterocyclyl;    -   amino; alkylamino; alkylcarbonyl; alkoxycarbonyl; alkylsulfanyl;        alkylsulfonyl; alkylsulfonyloxy

whose alkyl can be substituted with one or more of halo;

-   -   aminocarbonyl which can be N-substituted with one or two of        alkyl, aryl, arylalkyl;    -   aryl; arylalkyl; aryloxy; arylalkoxy; arylalkylsulfanyl;        heteroaryl; heteroaryloxy        -   whose (hetero)aryl part can be substituted with one or more            of amino, halo, alkyl, (poly)haloalkyl, hydroxyalkyl,            alkoxy, (poly)haloalkoxy, alkoxycarbonylamino,            alkylcarbonyl, alkylsulfanyl, nitro, cyanoalkyl, or is fused            with a non aromatic heterocycle;    -   heterocyclyloxy; heterocyclylalkoxy; heterocyclyl        -   whose heterocycle can be substituted with one or more of            halo, halogenoalkyl, acylamino, acyloxy, amino, alkyl,            alkylamino, dialkylamino, aminoalkyl, oxo, carbamimidoyl,            hydroxy, hydroxyalkyl;

or

-   -   fused with a non aromatic heterocycle (optionally substituted        with one or more of halogens) or carbocycle;        as well as their enantiomers, diastereomers, mixtures thereof        and pharmaceutically acceptable salts, tautomers, hydrates and        solvates.

Further group of compounds are those of formula (I) where:

X represents NH or S; and/or

HetAr represents a phenyl; and/or

R represents methyl; and/or

HET represents a piperidine or pyrrolidine; and/or

HET represents a piperidine; and/or

B represents a single bond; and/or

A represents 0 or NH;

Ar is a phenyl which can be optionally substituted with one or more of:

-   -   halo; azido; cyano; hydroxy; nitro; alkyl;    -   alkoxy; alkylsulfanyl; alkenyl; alkynyl; alkenyloxy; alkenyloxy;        -   whose alkyl; alkenyl or alkynyl part can be substituted with            one or more of halo, hydroxy, alkoxy, hydroxyalkoxy, cyano,            amino, alkylamino, aminoalkylamino, alkylsulfanyl,            alkylsulfonyl, cycloalkyl, (poly)cycloalkenyl, guanidino,            acylguanidino, alkoxycarbonylguanidino, alkoxycarbonyl,            alkoxycarbonylalkylamino, alkoxycarbonylheterocyclyl,            aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl,            alkylcarbonylalkoxy, aryloxy, arylsulfonyl, heteroaryl,            heterocyclyl, heterocyclylamino, hydrazinocarbonyl,            N-alkyl(thioureido), phthalimido, ureido,            oxocycloalkenylamino substituted with amino,            carbamimidoylheterocyclyl;    -   amino; alkylamino; alkylcarbonyl; alkoxycarbonyl; alkylsulfanyl;        alkylsulfonyl; alkylsulfonyloxy

whose alkyl can be substituted with one or more of halo;

-   -   aminocarbonyl which can be N-substituted with one or two of        alkyl, aryl, arylalkyl;    -   aryl; aryloxy; arylalkoxy; arylalkylsulfanyl; heteroaryl        -   whose aryl part can be substituted with one or more of            amino, halo, alkyl, (poly)haloalkyl, hydroxyalkyl, alkoxy,            (poly)haloalkoxy, alkoxycarbonylamino, alkylcarbonyl,            alkylsulfanyl, nitro, cyanoalkyl, or is fused with a non            aromatic heterocycle;    -   heterocyclyloxy; heterocyclylalkoxy        -   whose heterocycle can be substituted with one or more of            acylamino, acyloxy, amino, alkyl, carbamimidoyl, hydroxy,            hydroxyalkyl;

or

-   -   fused with a non aromatic heterocycle;

as well as their enantiomers, diastereomers, mixtures thereof andpharmaceutically acceptable salts, tautomers, hydrates and solvates.

In particular, the compounds of formula (I) may be chosen from those offormula (I′) below:

and (I″) below:

where

Ar is defined as above; and/or

i is 0, 1, 2, or 3; and/or

j is 0, 1, 2, or 3; and/or

Y is chosen from halo, hydroxy, alkyl, perhalogenoalkyl, alkoxy; and/or

Z is chosen from halo, hydroxy, alkyl, alkoxy.

More particularly, in formula (I′) and (I″):

i is 1, 2 or 3 and Y is chosen from halo, hydroxy, alkyl,perhalogenoalkyl, alkoxy; and/or

j is 0.

In one preferred embodiment, the present invention provides a compoundselected from the group consisting of:

-   2-[(1-methylpiperidin-4-yloxy)phenylmethyl]benzothiazole-   2-[(1-methylpyrrolidin-3-yloxy)phenylmethyl]benzothiazole-   2-[(4-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-[(4-chlorophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-[(3-fluorophenyl)(1-methylpiperidin-4-yloxymethyl]benzothiazole-   2-[(2-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-[(1-methylpiperidin-4-yloxy)-p-tolylmethyl]benzothiazole-   2-[(1-methylpiperidin-4-yloxy)(m-tolyl)methyl]benzothiazole    (benzothiazol-2-yl-phenylmethyl)(1-methylpiperidin-4-yl)amine-   2-[(2,3-dihydrobenzo[1,4]dioxin-6-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-[(3-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-[(2,4-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-[(1-methylpiperidin-4-yloxy)thiophen-2-ylmethyl]benzothiazole-   2-[(4-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-[(3,5-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-[(1-methylpiperidin-4-yloxy)thiophen-3-ylmethyl]benzothiazole-   2-[(1-methylpiperidin-4-yloxy)naphthalen-1-ylmethyl]benzothiazole-   2-[(1-methylpiperidin-4-yloxy)naphthalen-2-ylmethyl]benzothiazole-   2-[(1-methylpiperidin-4-yloxy)(5-methylthiophen-2-yl)methyl]benzothiazole-   2-[benzo[1,3]dioxol-5-yl(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   [(benzothiazol-2-yl)(m-tolyl)methyl](1-methylpiperidin-4-yl)amine-   2-[(3-allyloxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-[(1-methylpiperidin-4-yloxy)(3-trifluoromethoxyphenyl)methyl]benzothiazole-   2-[(1-methylpiperidin-4-yloxy)(4-trifluoromethoxyphenyl)methyl]benzothiazole-   [benzothiazol-2-yl(3-methoxyphenyl)methyl](1-methylpiperidin-4-yl)amine-   2-[(1-methylpiperidin-4-yloxy)(3-propoxy-phenyl)methyl]benzothiazole-   2-[(3-bromo-phenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-[(1-methylpiperidin-4-yloxy)(3-phenoxy-phenyl)methyl]benzothiazole-   5-methyl-2-[(1-methylpiperidin-4-yloxy)phenylmethyl]benzothiazole-   2-[(1-methylpiperidin-4-yloxy)phenylmethyl]-1H-benzimidazole-   2-[(1-methylpiperidin-4-yloxy)(3-trifluoromethylphenyl)methyl]benzothiazole-   2-[(2,3-dihydrobenzofuran-5-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   5-fluoro-2-[(1-methylpiperidin-4-yloxy)phenylmethyl]benzothiazole-   2-[(4-fluoro-3-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   [benzothiazol-2-yl(4-fluoro-3-methyl-phenyl)methyl](1-methylpiperidin-4-yl)amine-   (benzothiazol-2-yl-p-tolylmethyl)(1-methylpiperidin-4-yl)amine-   [(benzofuran-2-yl)(benzothiazol-2-yl)methyl](1-methylpiperidin-4-yl)amine-   2-[(3-fluoro-5-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   [(1H-benzimidazol-2-yl)phenylmethyl](1-methylpiperidin-4-yl)amine-   2-[(3-fluoro-5-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   [benzothiazol-2-yl(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amine-   [benzothiazol-2-yl(3-fluoro-5-methoxyphenyl)methyl](1-methylpiperidin-4-yl)amine-   [benzothiazol-2-yl(3-fluoro-5-methylphenyl)methyl](1-methylpiperidin-4-yl)amine-   2-[(3-benzyloxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-[benzofuran-5-yl(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-[(3-ethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   [benzothiazol-2-yl(3-iodophenyl)methyl](1-methylpiperidin-4-yl)amine-   2-[(1-methylpiperidin-4-yloxy)(3-propoxyphenyl)methyl]-1H-benzimidazole-   [(1H-benzimidazol-2-yl)(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amine-   2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   (benzothiazol-2-ylpyridin-3-ylmethyl)(1-methylpiperidin-4-yl)amine-   2-[biphenyl-3-yl(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   {3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxymethyl]biphenyl-3-yl}methanol-   2-[(3-isopropoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   [benzothiazol-2-yl(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amine-   [benzothiazol-2-yl(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amine-   [benzothiazol-2-yl(1H-pyrrol-2-yl)methyl](1-methylpiperidin-4-yl)amine-   [(1H-benzimidazol-2-yl)(3-trifluoromethylphenyl)methyl](1-methylpiperidin-4-yl)amine-   [(1H-benzimidazol-2-yl)(3-trifluoromethoxyphenyl)methyl](1-methylpiperidin-4-yl)amine-   [(1H-benzimidazol-2-yl)(3-ethylphenyl)methyl](1-methylpiperidin-4-yl)amine-   3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenol-   2-[(1-methylpiperidin-4-yloxy)(3-pyridin-3-ylphenyl)methyl]benzothiazole-   [(1H-benzimidazol-2-yl)(3-bromophenyl)methyl](1-methylpiperidin-4-yl)amine-   [(1H-benzimidazol-2-yl)(3-benzyloxyphenyl)methyl](1-methylpiperidin-4-yl)amine-   [(1H-benzimidazol-2-yl)(3-isopropylphenyl)methyl](1-methylpiperidin-4-yl)amine-   [(1H-benzimidazol-2-yl)(3-isobutoxyphenyl)methyl](1-methylpiperidin-4-yl)amine-   {(1H-benzimidazol-2-yl)[3-(3-methylbutoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine-   [(1H-benzimidazol-2-yl)(3-butoxyphenyl)methyl](1-methylpiperidin-4-yl)amine-   [(1H-benzimidazol-2-yl)(3-methoxyphenyl)methyl](1-methylpiperidin-4-yl)amine-   trifluoromethanesulfonic acid    3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl ester-   trifluoromethanesulfonic acid    3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl ester-   [(1H-benzimidazol-2-yl)(3-cyclohexyl    methoxyphenyl)methyl](1-methylpiperidin-4-yl)amine-   [(1H-benzimidazol-2-yl)(3-fluorophenyl)methyl](1-methylpiperidin-4-yl)amine-   [(1H-benzimidazol-2-yl)(3-methylsulfanylphenyl)methyl](1-methylpiperidin-4-yl)amine-   [(1H-benzimidazol-2-yl)(3-hexylphenyl)methyl](1-methylpiperidin-4-yl)amine-   [(1H-benzimidazol-2-yl)(3-isopropoxyphenyl)methyl](1-methylpiperidin-4-yl)amine-   2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-ylamine-   2-[(3-butylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-[biphenyl-3-yl(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   [benzothiazol-2-yl(3-bromophenyl)methyl](1-methylpiperidin-4-yl)amine-   [(1H-benzimidazol-2-yl)(3-ethoxyphenyl)methyl](1-methylpiperidin-4-yl)amine-   [(1H-benzimidazol-2-yl)(m-tolyl)methyl](1-methylpiperidin-4-yl)amine-   [(1H-benzimidazol-2-yl)(3-phenoxyphenyl)methyl](1-methylpiperidin-4-yl)amine-   {3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-yl}methanol-   3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-ylamine-   [benzothiazol-2-yl(3-isopropoxyphenyl)methyl](1-methylpiperidin-4-yl)amine-   2-[(1-methylpiperidin-4-yloxy)(3-pyridin-3-ylphenyl)methyl]-1H-benzimidazole-   1-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-ylamino)methyl]phenyl}ethanone-   [benzothiazol-2-yl(3-butoxyphenyl)methyl](1-methylpiperidin-4-yl)amine-   2-[(3-butoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   [benzothiazol-2-yl(3-cyclohexylmethoxyphenyl)methyl](1-methylpiperidin-4-yl)amine-   [(1H-benzimidazol-2-yl)biphenyl-3-ylmethyl](1-methylpiperidin-4-yl)amine-   [(1H-benzimidazol-2-yl)(3-pentyloxyphenyl)methyl](1-methylpiperidin-4-yl)amine-   2-[(2′-methoxybiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-[(1-methylpiperidin-4-yloxy)(3′-nitrobiphenyl-3-yl)methyl]benzothiazole-   {3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-yl}acetonitrile-   2-[(3′-methoxybiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-[(4′-methoxybiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   [benzothiazol-2-yl(3-benzyloxyphenyl)methyl](1-methylpiperidin-4-yl)amine-   (benzothiazol-2-ylbiphenyl-3-ylmethyl)(1-methylpiperidin-4-yl)amine-   {(1H-benzimidazol-2-yl)[3-(4-fluorobenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine-   [(1H-benzimidazol-2-yl)(3-benzylsulfanylphenyl)methyl](1-methylpiperidin-4-yl)amine-   {(1H-benzimidazol-2-yl)[3-(3-fluorobenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine-   {(1H-benzimidazol-2-yl)[3-(2-phenoxyethoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine-   [benzothiazol-2-yl(3-benzylsulfanylphenyl)methyl](1-methylpiperidin-4-yl)amine-   1-{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-4-yl}ethanone-   2-[(3′-fluoro-biphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   1-{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-yl}ethanone-   [benzothiazol-2-yl(3-methylsulfanylphenyl)methyl](1-methylpiperidin-4-yl)amine-   [(3-allyloxyphenyl)(1H-benzimidazol-2-yl)methyl](1-methylpiperidin-4-yl)amine-   {(1H-benzimidazol-2-yl)[3-(2-fluorobenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine-   2-[(1-methylpiperidin-4-yloxy)(2′-methylsulfanylbiphenyl-3-yl)methyl]-1H-benzimidazole-   2-[(4′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[(1-methylpiperidin-4-yloxy)(3′-methylsulfanylbiphenyl-3-yl)methyl]-1H-benzimidazole-   2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-[(1-methylpiperidin-4-yloxy)(4′-trifluoromethylbiphenyl-3-yl)methyl]-1H-benzimidazole-   {(1H-benzimidazol-2-yl)[3-(tetrahydropyran-2-yloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine-   2-[(2′-chlorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[(3′,4′-dichlorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   {3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-2-yl}methanol-   {(1H-benzimidazol-2-yl)[3-(4-methoxybenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine-   {(1H-benzimidazol-2-yl)[3-(3-methoxybenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine-   3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-ylamino)methyl]phenol-   {3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]biphenyl-2-yl}methanol-   2-[(1-methylpiperidin-4-yloxy)(3′-methylsulfanylbiphenyl-3-yl)methyl]benzothiazole-   {(1H-benzimidazol-2-yl)[3-(2-methylbenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine-   {(1H-benzimidazol-2-yl)[3-(4-methylbenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine-   [(1H-benzimidazol-2-yl)(3-nitrophenyl)methyl](1-methylpiperidin-4-yl)amine-   [(3-azidophenyl)(1H-benzimidazol-2-yl)methyl](1-methylpiperidin-4-yl)amine-   2-[(3′,4′-dichlorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   {(1H-benzimidazol-2-yl)[3-(2-ethoxyethoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine-   [(1H-benzimidazol-2-yl)(3-pent-4-enyloxyphenyl)methyl](1-methylpiperidin-4-yl)amine-   2-[(4′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-[(2′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   {3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-4-yl}carbamic    acid tert-butyl ester-   2-[(3′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-[(1-methylpiperidin-4-yloxy)(4′-trifluoromethylbiphenyl-3-yl)methyl]benzothiazole-   2-[(1-methylpiperidin-4-yloxy)(2′,3′,4′-trifluorobiphenyl-3-yl)methyl]benzothiazole-   2-[(2′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   {3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]biphenyl-4-yl}carbamic    acid tert-butyl ester-   [(1H-benzimidazol-2-yl)(3-furan-2-ylphenyl)methyl](1-methylpiperidin-4-yl)amine-   [(1H-benzimidazol-2-yl)(3-but-3-enyloxyphenyl)methyl](1-methylpiperidin-4-yl)amine-   {(1H-benzimidazol-2-yl)[3-(4-methylpentyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine-   2-[(1-methylpiperidin-4-yloxy)(3-pyrazol-1-ylphenyl)methyl]benzothiazole-   2-[(3-benzylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   {(1H-benzimidazol-2-yl)[3-(2,5-difluoro-benzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine-   2-[(3-benzylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[(2-chlorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[(3-ethylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-[(3-ethylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   {3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetic    acid methyl ester-   2-[(3-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[[3-(2,5-difluorobenzyloxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanol-   2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanol-   2-[(3-ethylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   {3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetic    acid methyl ester-   2-[[3-(2,3-difluorobenzyloxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole-   {(1H-benzimidazol-2-yl)[3-(2,3-difluoro-benzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine-   2-[[3-(2-fluoroethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-[(1-methylpiperidin-4-yloxy)(m-tolyl)methyl]-1H-benzimidazole-   5,6-dichloro-2-[(1-methylpiperidin-4-yloxy)phenyl-methyl]-1H-benzimidazole-   5-fluoro-2-[(1-methylpiperidin-4-yloxy)phenyl-methyl]-1H-benzimidazole-   2-[(2-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[(1-methylpiperidin-4-yloxy)(3-pent-4-enyloxy-phenyl)methyl]benzothiazole-   2-{(1-methylpiperidin-4-yloxy)[3-(4,4,4-trifluoro-butoxy)phenyl]methyl}benzothiazole-   5-bromo-2-[(1-methylpiperidin-4-yloxy)phenyl-methyl]-1H-benzimidazole-   2-[[3-(3-fluorobenzyloxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole-   3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzonitrile-   2-[[3-(furan-2-ylmethylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   ((1H-benzimidazol-2-yl)-{3-[3-(2-methyl-[1,3]dioxolan-2-yl)-propoxy]phenyl}methyl)(1-methylpiperidin-4-yl)amine-   {(1H-benzimidazol-2-yl)[3-(4,4,4-trifluoro-butoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine-   2-[[3-(3-fluoropropoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-[(1-methylpiperidin-4-yloxy)-p-tolyl-methyl]-1H-benzimidazole-   2-{(1-methylpiperidin-4-yloxy)[3-(3,3,3-trifluoro-propoxy)phenyl]methyl}benzothiazole-   2-[(4-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   {(1H-benzimidazol-2-yl)[3-(2-fluoro-ethoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine-   ((1H-benzimidazol-2-yl)-{3-[2-(6,6-dimethyl-bicyclo[3.1.1]hept-2-en-2-yl)ethoxy]phenyl}methyl)(1-methylpiperidin-4-yl)amine-   2-[(1-methylpiperidin-4-yloxy)(4′-trifluoromethoxy-biphenyl-3-yl)methyl]-1H-benzimidazole-   2-[(4′-methoxybiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[(3-benzo[1,3]dioxol-5-ylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[[3-(3-methoxybenzyloxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole-   5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentan-2-one-   2-{(1-methylpiperidin-4-yloxy)[3-(3-trifluoromethyl-benzyloxy)phenyl]methyl}benzothiazole-   4-[benzothiazol-2-yl(3-bromo-phenyl)methoxy]-1,1-dimethylpiperidinium-   2-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)isoindole-1,3-dione-   3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-yn-1-ol-   4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-yn-1-ol-   5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-yn-1-ol-   2-[(1-methylpiperidin-4-yloxy)-o-tolyl-methyl]-1H-benzimidazole-   3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynylamine-   2-[(3-ethynylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-{(1-methylpiperidin-4-yloxy)[3-(3-nitro-benzyloxy)phenyl]methyl}benzothiazole-   3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]benzonitrile-   2-{(1-methylpiperidin-4-yloxy)[3-(1H-[1,2,3]triazol-4-yl)phenyl]methyl}-1H-benzimidazole-   3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]benzoic acid    methyl ester-   2-[(1-methylpiperidin-4-yloxy)phenyl-methyl]-3H-benzimidazol-4-ylamine-   2-[(1-methylpiperidin-4-yloxy)(3-methylsulfanyl-phenyl)methyl]benzothiazole-   2-[(1-methylpiperidin-4-yloxy)(3-methylsulfanyl-phenyl)methyl]-1H-benzimidazole-   2-[(3-methanesulfonylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-[(4-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}acrylic    acid tert-butyl ester-   3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]benzoic acid    ethyl ester-   {3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}methanol-   3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}propionic    acid tert-butyl ester-   2-[[3-(2-benzenesulfonylvinyl)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-[(1-methylpiperidin-4-yloxy)phenyl-methyl]-3H-benzimidazol-4-ol-   [benzothiazol-2-yl(4′-methoxy-biphenyl-3-yl)methyl](1-methylpiperidin-4-yl)amine-   2-[[3-(2-methanesulfonylvinyl)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-[(2-chloro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrimidin-2-ol-   2-[(3-tert-butylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[(1-methylpiperidin-4-yloxy)(3-pyrimidin-5-yl-phenyl)methyl]benzothiazole-   3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}acrylonitrile-   2-[(1-methylpiperidin-4-yloxy)(3-vinyl-phenyl)methyl]benzothiazole-   3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]-N-benzyl-N-methylbenzamide-   3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]-N-propylbenzamide-   2-[(2,4-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   [(1H-benzimidazol-2-yl)(4′-methoxy-biphenyl-3-yl)methyl](1-methylpiperidin-4-yl)amine-   3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]-N-methyl-N-phenylbenzamide-   3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylamine-   2-[(3-chlorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[(4-chlorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-yn-1-ol-   3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxymethyl}-phenylamine-   2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanol-   2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanol-   2-[(3-azidophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-{(1-methylpiperidin-4-yloxy)[3-(2-pyrazin-2-yl-ethylsulfanyl)phenyl]methyl}-1H-benzimidazole-   2-{(1-methylpiperidin-4-yloxy)[3-(2-pyrazin-2-yl-ethylsulfanyl)phenyl]methyl}benzothiazole-   {3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}benzyl-amine-   3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-3-methyl-butan-1-ol-   4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-yn-1-ol-   5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-yn-1-ol-   4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}butan-1-ol-   (1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}-cyclopropyl)acetic    acid methyl ester-   2-{(1-methylpiperidin-4-yloxy)[3-(2-[1,2,3]triazol-2-yl-ethylsulfanyl)phenyl]methyl}benzothiazole-   2-{(1-methylpiperidin-4-yloxy)[3-(2-[1,2,3]triazol-1-yl-ethylsulfanyl)phenyl]methyl}benzothiazole-   3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-3-methyl-butan-1-ol-   2-[(1-methylpiperidin-4-yloxy)(3-morpholin-4-yl-phenyl)methyl]benzothiazole-   2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethanol-   2-[(1-methylpiperidin-4-yloxy)(3-vinyl-phenyl)methyl]-1H-benzimidazole-   3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propan-1-ol-   1-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propan-2-ol-   4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butan-1-ol-   2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine-   2-{(1-methylpiperidin-4-yloxy)[3-(2-methylsulfanyl-ethoxy)phenyl]methyl}benzothiazole-   2-[(1-methylpiperidin-4-yloxy)(2-trifluoromethoxy-phenyl)methyl]-1H-benzimidazole-   2-[(1-methylpiperidin-4-yloxy)-p-tolylmethyl]-1H-benzimidazole-   2-[(1-methylpiperidin-4-yloxy)-p-tolyl-methyl]-1H-benzimidazole-   3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propan-1-ol-   1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propan-2-ol-   4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butan-1-ol-   2-(1-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}-cyclopropyl)ethanol-   3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}propan-1-ol-   2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-N-methylacetamide-   2-{(1-methylpiperidin-4-yloxy)[3-(2H-pyrazol-3-yl)phenyl]methyl}benzothiazole-   2-[(3-bromo-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[(2-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetamide-   {3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetic    acid hydrazide-   2-{(1-methylpiperidin-4-yloxy)[3-(pyridin-4-ylmethoxy)phenyl]methyl}benzothiazole-   4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}butan-1-ol-   2[[3-(furan-2-ylmethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}-cyclopropyl)ethanol-   2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine-   1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]benzyloxy}propan-2-one-   2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethylamine-   2-[(1-methylpyrrolidin-3-yloxy)phenyl-methyl]-1H-benzimidazole-   [(1H-benzimidazol-2-yl)-p-tolyl-methyl](1-methylpiperidin-4-yl)amine-   2-[(3-ethylsulfanyl-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   1-(3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyloxy)-propan-2-one-   1-(3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyloxy)-propan-2-ol-   2[[3-(2-methoxyethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole-   N-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine-   (2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethyl)methyl-amine-   2-[(1-methylpiperidin-4-yloxy)(3-trifluoromethoxy-phenyl)methyl]-1H-benzimidazole-   2-[(2-chlorophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynylamine-   2-{(1-methylpiperidin-4-yloxy)[3-(pyridin-2-ylmethoxy)phenyl]methyl}benzothiazole-   2-{(1-methylpiperidin-4-yloxy)[3-(pyridin-3-ylmethoxy)phenyl]methyl}benzothiazole-   2-[(3-Cyclohexylmethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynylamine-   5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine-   3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propane-1,2-diol-   5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pentylamine-   2-{3-[benzothiazol-2-yl(1-ethyl-piperidin-4-yloxy)methyl]phenoxy}ethylamine-   2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethylamine-   6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}hexan-1-ol-   4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}butylamine-   5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine-   6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}hexan-1-ol-   3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynylamine-   2-[benzo[1,3]dioxol-5-yl(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   (2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)-urea-   (2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)(4,5-dihydro-thiazol-2-yl)amine-   2-[(2,3-dihydrobenzo[1,4]dioxin-6-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}butylamine-   N-(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine-   3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}propylamine-   N-tert-butoxycarbonyl-N′-(2-{3-[(benzothiazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine-   5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}pentylamine-   2[{3-[2-(1-methyl-1H-imidazol4-yl)ethyl]phenyl}(1-methylpiperidin-4-yloxy)methyl]benzothiazole-   N-tert-butoxycarbonyl-N′-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynyl)guanidine-   N-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}butyl)guanidine-   N-tert-butoxycarbonyl-N′-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}butyl)guanidine-   2-{(1-methylpiperidin-4-yloxy)[3-(pyridin-2-ylmethoxy)phenyl]methyl}-1H-benzimidazole-   3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}propylamine-   5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pentylamine-   N-tert-butoxycarbonyl-N′-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}propyl)guanidine-   3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propylamine-   2-{(1-methylpiperidin-4-yloxy)[3-(4-[1,2,3]triazol-2-yl-butoxy)phenyl]methyl}benzothiazole-   2-{(1-methylpiperidin-4-yloxy)[3-(4-[1,2,4]triazol-1-yl-butoxy)phenyl]methyl}benzothiazole-   (2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)(4,5-dihydro-1H-imidazol-2-yl)amine-   N-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)-N′-cyanoguanidine-   6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynylamine-   N-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}propyl)guanidine-   N-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}propyl)guanidine-   2-{(1-methylpiperidin-4-yloxy)[3-(4-morpholin-4-yl-butoxy)phenyl]methyl}benzothiazole-   (1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-2-yl)methanol-   (1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-2-yl)methanol-   6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}hexylamine-   4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butylamine-   3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}propylamine-   4-(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethyl)piperazine-1-carboxylic    acid tert-butyl ester-   4-(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethyl)piperazine-1-carboxylic    acid tert-butyl ester-   2-{(1-methylpiperidin-4-yloxy)[3-(2-piperazin-1-yl-ethoxy)phenyl]methyl}benzothiazole-   4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}butylamine-   2-{(1-methylpiperidin-4-yloxy)[3-(4-morpholin-4-yl-butoxy)phenyl]methyl}-1H-benzimidazole-   2-{(1-methylpiperidin-4-yloxy)[3-(4-piperidin-1-yl-butoxy)phenyl]methyl}-1H-benzimidazole-   2-[(2-fluoro-3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   N-tert-butoxycarbonyl-N′-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pentyl)guanidine-   N-tert-butoxycarbonyl-N′-(3-{3-[(1H-benzimidazol-2-yl)(1-methyl    piperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)guanidine-   6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynylamine-   2-{(1-methylpiperidin-4-yloxy)[3-(1,2,3,6-tetrahydro-pyridin-4-yl)phenyl]methyl}-1H-benzimidazole-   N-tert-butoxycarbonyl-N′-(5-{3-[(benzothiazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-5-ynyl)guanidine-   N-(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)guanidine-   N-tert-butoxycarbonyl-N′-(6-{3-[(benzothiazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)guanidine-   N-(6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)guanidine-   4-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}butyl)piperazine-1-carboxylic    acid tert-butyl ester-   6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hexylamine-   N-tert-butoxycarbonyl-N′-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)guanidine-   N-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)guanidine-   1-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)-3-isopropyl-thiourea-   2-{(1-methylpiperidin-4-yloxy)[3-(3-[1,2,4]triazol-1-yl-propoxy)phenyl]methyl}benzothiazole-   2-{(1-methylpiperidin-4-yloxy)[3-(3-[1,2,3]triazol-2-yl-propoxy)phenyl]methyl}benzothiazole-   2-{(1-methylpiperidin-4-yloxy)[3-(3-morpholin-4-yl-propoxy)phenyl]methyl}benzothiazole-   4-(3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}propyl)piperazine-1-carboxylic    acid tert-butyl ester-   2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-phenylsulfanyl}ethylamine-   4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}-3,6-dihydro-2H-pyridine-1-carboxamidine-   2[[3-(2-chloroethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole-   N-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hexyl)guanidine-   2-{(1-methylpiperidin-4-yloxy)[3-(2-piperidin-1-yl-ethoxy)phenyl]methyl}-1H-benzimidazole-   N-tert-butoxycarbonyl-N′-(5-{3-[(1H-benzimidazol-2-yl)(1-methyl    piperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)guanidine-   N-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)guanidine-   4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butylamine-   4-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}propyl)piperazine-1-carboxylic    acid tert-butyl ester-   (2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethylamino)acetic    acid tert-butyl ester-   4-(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentyl)piperazine-1-carboxylic    acid tert-butyl ester-   N-(6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}hexyl)guanidine-   N-tert-butoxycarbonyl-N′-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hexyl)guanidine-   N-(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pentyl)guanidine-   4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}butylamine-   [[3-(4-aminobutoxy)phenyl](1H-benzimidazol-2-yl)methyl](1-methylpiperidin-4-yl)amine-   3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propylamine-   4-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethyl)piperazine-1-carboxylic    acid tert-butyl ester-   (2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethylamino)acetic    acid tert-butyl ester-   5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentylamine-   N-(4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynyl)guanidine-   N-(3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)guanidine-   N-(4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}butyl)guanidine-   (5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentylamino)acetic    acid tert-butyl ester-   2-[(1-methylpiperidin-4-yloxy)(3-piperidin-4-ylethynyl-phenyl)methyl]-1H-benzimidazole-   2-{(1-methylpiperidin-4-yloxy)[3-(piperidin-4-ylmethoxy)phenyl]methyl}benzothiazole-   2-{(1-methylpiperidin-4-yloxy)[3-(piperidin-3-ylmethoxy)phenyl]methyl}benzothiazole-   2[[3-(1-methylpiperidin-3-ylmethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole-   2-[(1-methylpiperidin-4-yloxy)(3-piperidin-3-ylethynyl-phenyl)methyl]-1H-benzimidazole-   5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}pentylamine-   2-{(1-methylpiperidin-4-yloxy)[3-(pyrrolidin-3-yloxy)phenyl]methyl}benzothiazole-   2-{(1-methylpiperidin-4-yloxy)[3-(pyrrolidin-3-yloxy)phenyl]methyl}benzothiazole-   5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-en-1-ol-   3-amino-4-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamino)-cyclobut-3-ene-1,2-dione-   [[3-(6-aminohex-1-ynyl)phenyl](1H-benzimidazol-2-yl)methyl](1-methylpiperidin-4-yl)amine-   {[3-(4-aminobutoxy)phenyl]benzothiazol-2-yl-methyl}(1-methylpiperidin-4-yl)amine-   2-[(3-azetidin-3-ylethynylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-en-1-ol-   5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-en-1-ol-   4-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentyl)piperazine-1-carboxylic    acid tert-butyl ester-   2[[3-(2-azetidin-3-ylethyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   N-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynyl)guanidine-   4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}piperidine-1-carboxamidine-   2-{(1-methylpiperidin-4-yloxy)[3-(2-piperidin-2-yl-ethylsulfanyl)phenyl]methyl}-1H-benzimidazole-   2-{(1-methylpiperidin-4-yloxy)[3-(2-piperidin-4-yl-ethyl)phenyl]methyl}-1H-benzimidazole-   N-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pentyl)guanidine-   2-[{3-[3-(3H-imidazol-4-yl)propylsulfanyl]phenyl}(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   N-tert-butoxycarbonyl-N′-(4-{3-[(benzothiazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynyl)guanidine-   5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentylamine-   N-acetyl-N′-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine-   2[[3-(azetidin-3-yloxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole-   1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}azetidin-3-ol-   (1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)methanol-   1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}piperidin-4-ylamine-   1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ol-   1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ol-   N-(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)acetamide-   2[[3-(5-imidazol-1-ylpent-1-ynyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-{(1-methylpiperidin-4-yloxy)[3-(5-pyrazol-1-yl-pent-1-ynyl)phenyl]methyl}-1H-benzimidazole-   1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}piperidin-4-ol-   2-[{3-[2-(1H-imidazol-4-yl)ethyl]phenyl}(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   acetic acid    1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}piperidin-4-yl    ester-   2-[(3-bromo-phenyl)(1-methyl-pyrrolidin-3-ylmethoxy)methyl]-1H-benzimidazole-   2-{(1-methylpiperidin-4-yloxy)[3-(piperidin-4-yloxy)phenyl]methyl}benzothiazole-   2-{(1-methylpiperidin-4-yloxy)[3-(5-[1,2,3]triazol-2-yl-pent-1-ynyl)phenyl]methyl}-1H-benzimidazole-   2-{(1-methylpiperidin-4-yloxy)[3-(5-[1,2,3]triazol-1-yl-pent-1-ynyl)phenyl]methyl}-1H-benzimidazole-   N-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)guanidine-   N1-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentyl)butane-1,4-diamine-   {[3-(6-aminohex-1-ynyl)phenyl]benzothiazol-2-yl-methyl}(1-methylpiperidin-4-yl)amine-   5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-enylamine-   4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}but-2-en-1-ol-   1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ylamine-   2-[(2,5-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[(2-fluoro-5-iodo-phenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylethynyl}azetidine-1-carboxamidine-   4-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butan-1-ol-   2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine-   1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ylamine-   2[[3-(3-fluoropyrrolidin-1-yl)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole-   4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}but-2-enylamine-   2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole    (enantiomer A)-   2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole    (enantiomer B)-   N-(2-aminoethyl)-2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetamide-   N-(2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine-   2-(5-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)isoindole-1,3-dione-   6-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynylamine    oxalate-   4-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butylamine    oxalate-   N-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propyl)guanidine,    dihydrochloride-   1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-one,    oxalate-   N-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butyl)guanidine,    dihydrochloride-   5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}pentan-1-ol-   N-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)-N-(2,2-dimethylpropionyl)guanidine-   2-[(1-methylpiperidin-4-yloxy)(4-nitrophenyl)methyl]-1H-benzimidazole-   2-{(1-methylpiperidin-4-yloxy)[3-(pyridin-3-yloxy)phenyl]methyl}benzothiazole,    oxalate-   2-[(3-bromophenyl)(1-methylpyrrolidin-3-ylmethoxy)methyl]-5-fluoro-1H-benzimidazole,    oxalate-   4-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]aniline-   4-[(1H-benzimidazol-2-yl)(piperidin-4-yloxy)methyl]aniline,    hydrochloride-   N-(2-amino-ethyl)-2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetamide-   1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}-3-trifluoromethylpyrrolidin-3-ol,    oxalate-   2-[[3-(4,5-dihydro-1H-imidazol-2-ylmethylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[[3-(4,5-dihydro-1H-imidazol-2-ylmethylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole-   2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5,6-difluoro-1H-benzimidazole-   2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1-methyl-1H-benzimidazole,    dioxalate-   2-amino-5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}-1,5-dihydroimidazol-4-one-   2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5,6,7-trifluoro-1H-benzimidazole-   1-(2-ethoxyethyl)-2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,    dioxalate-   3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzaldehyde-   4-{3-[(1H-benzimidazol-2-yl)(1-methylazetidin-3-ylmethoxy)methyl]phenylsulfanyl}butylamine,    oxalate-   2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzoxazole,    oxalate-   {3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}methanol.    dimethylsulfoxonium ylide of 3-bromophenylacetic acid methyl ester-   2-[(2-fluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,    enantiomer B-   2-[(2,6-difluoro-3-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   ethyl    (6-{3-[(1-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)carbamate,    oxalate-   2-[(1H-indol-6-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,    oxalate-   2-[benzo[b]thiophen-6-yl(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,    oxalate-   2-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,    enantiomer B-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol-   2-[(1H-benzimidazol-2-yl)hydroxymethyl]phenol-   2-[(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylimino)phenylmethyl]phenol-   5-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylimino)-2-methylcyclopent-1-enol-   2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,    enantiomer B-   5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine,    enantiomer A-   5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine,    enantiomer B-   2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole,    enantiomer A-   2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole,    enantiomer B-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-methylphenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol    enantiomer A-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol    enantiomer B-   6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-3-methylphenol    enantiomer A-   6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-3-methylphenol    enantiomer B-   6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2,3-difluorophenol    enantiomer A-   6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2,3-difluorophenol    enantiomer B-   5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}pent-4-ynylamine,    dioxalate-   3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}cyclopentylamine,    oxalate-   2-{[3-(3-fluoropyrrolidin-1-yl)phenyl](1-methylpiperidin-4-yloxy)methyl}benzothiazole,    oxalate-   5-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpyrrolidin-3-ylmethoxy)methyl]phenyl}pent-4-ynylamine,    oxalate-   2-[(3-bromophenyl)(1-methylpyrrolidin-3-ylmethoxy)methyl]benzothiazole,    oxalate (one epimer)-   2-[(3-bromophenyl)(1-methylpyrrolidin-3-ylmethoxy)methyl]benzothiazole,    oxalate (50/50 mixture of two epimers)-   2-{(1-methylpiperidin-4-yloxy)[3-(octahydrocyclopenta[c]pyrrol-5-yloxy)phenyl]methyl}benzothiazole,    dioxalate-   (1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)methylamine,    dioxalate-   4-{3-[(5,6-difluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butan-1-ol-   2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}octahydrocyclopenta[c]pyrrol-5-ylamine,    dioxalate-   2-{[3-(3-fluoropropoxy)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H-benzimidazole,    oxalate-   2-{[3-(2-fluoroethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H-benzimidazole,    oxalate-   4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}cyclohexylamine,    oxalate-   6-{3-[(1-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynylamine,    dioxalate-   1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-2-ylmethylamine,    oxalate-   (1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)(methyl)amine,    oxalate-   (1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)(dimethyl)amine,    oxalate-   2-{[3-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2-yl)phenyl](1-methylpiperidin-4-yloxy)methyl}benzothiazole,    dioxalate-   2-[(2-fluoro-5-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,    oxalate-   3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenol,    oxalate-   2-{[2-fluoro-5-(2-fluoroethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H-benzimidazole,    oxalate-   2-[(2-fluoro-5-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,    oxalate-   4-{3-[(1-methylpiperidin-4-yloxy)(5,6,7-trifluoro-1H-benzimidazol-2-yl)methyl]phenylsulfanyl}butylamine,    oxalate-   4-{3-[(5,6-difluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butylamine,    oxalate-   6-(3-{[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl](1-methylpiperidin-4-yloxy)methyl}phenyl)hex-5-ynylamine,    dioxalate-   6-(3-{[1-(2-methoxyethyl)-1H-benzimidazol-2-yl](1-methylpiperidin-4-yloxy)methyl}phenyl)hex-5-ynylamine,    dioxalate-   2-{[3-(3-fluoropropylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H-benzimidazole,    dioxalate-   5-fluoro-2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,    oxalate-   4,5,6-trifluoro-2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   5,6-difluoro-2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-{[2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H-benzimidazole-   2-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[(2-chloro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,    oxalate-   2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole,    oxalate-   2-[(4-chloro-2,6-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   7-fluoro-2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,    oxalate-   2-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole,    oxalate-   2-[(4-chloro-2,6-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole,    oxalate-   2-[(3-ethoxy-2,6-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzoxazole,    oxalate-   2-[(1-methylpiperidin-4-yloxy)(4-trifluoromethylphenyl)methyl]-1H-benzimidazole-   2-[(2-fluoro-4-trifluoromethylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[(2,4-dimethylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[(3-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[chroman-7-yl(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[(2-fluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzoxazole,    oxalate-   2-[(3,5-bis-trifluoromethylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,    oxalate-   5-fluoro-2-[(2-fluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[(2,3-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[(3-chloro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   ethyl    2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzimidazole-1-carboxylate,    oxalate-   2-[(3-fluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[(5-bromo-2-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylamine,    oxalate-   5-{4-fluoro-3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine-   ethyl    (5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}pent-4-ynyl)carbamate-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-chlorophenol-   ethyl    (5-{4-fluoro-3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)carbamate-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-trifluoromethoxyphenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-methoxyphenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-methylphenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-bromophenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-ethoxyphenol-   2-[(1H-indol-7-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4,6-difluorophenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4,6-dichlorophenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-3-fluorophenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4,5-difluorophenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-fluorophenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-chlorophenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-methylphenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-methylsulfanylphenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-ethylsulfanylphenol-   3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-4-ol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-tert-butyl    phenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-propylphenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-methoxyphenol-   2-[(1H-benzimidazol-2-yl)(1-methy-piperidin-4-yloxy)methyl]-3-fluoro-5-methylphenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-3-chlorophenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluoro-4-ethylphenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-benzylphenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-trifluoromethylphenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-chloro-6-fluorophenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-3-methylphenol-   6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-3-methylphenol-   6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]indan-5-ol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-propoxyphenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-(1-methyl-1-phenylethyl)phenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-(2-fluoroethoxy)phenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-(3-fluoropropoxy)phenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluoro-6-methylphenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluoro-4-methoxyphenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-phenoxyphenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluoro-6-methoxyphenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4,5-dimethylphenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-(3-fluoropropylsulfanyl)phenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluoro-5-methylphenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-(2-fluoroethylsulfanyl)phenol-   3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-hydroxybiphenyl-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-ethylphenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-trifluoromethylphenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-hydroxyphenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5,6,7,8-tetrahydro-1-naphthol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-trifluoromethoxyphenol-   2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-trifluoromethoxyphenol-   6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-3,4-dimethylphenol-   6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-3-fluoro-2-methylphenol-   6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2,4-difluoro-3-methylphenol-   6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2,3-difluorophenol-   (1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}-azetidin-3-yl)dimethylamine,    oxalate-   1-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ol,    oxalate-   2-{(1-methylpiperidin-4-yloxy)[3-(pyrrolidin-3-yloxy)phenyl]methyl}-1H-benzimidazole,    dioxalate-   2-[(5-chloro-2-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,    oxalate-   2-[(2-fluoro-5-trifluoromethylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,    oxalate-   6-{3-[(1-ethyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynylamine,    oxalate-   2-[(2-fluoro-5-methoxyphenyl)(1-methylpyrrolidin-3-ylmethoxy)methyl]-1H-benzimidazole,    oxalate-   2-[(1-methylpiperidin-4-yloxy)(3-trifluoromethylsulfanylphenyl)methyl]-1H-benzimidazole,    oxalate-   2-[(4-fluoro-3-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,    oxalate-   2-[(2-fluoro-5-propoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,    oxalate-   4-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol-   2-{[3-(3,3-difluoropyrrolidin-1-yl)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H-benzimidazole,    dioxalate-   2-{[3-(5-fluorohexahydrocyclopenta[c]pyrrol-2-yl)phenyl](1-methylpiperidin-4-yloxy)methyl}benzothiazole,    dioxalate-   6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}hexylamine,    oxalate-   5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}oxazolidin-2-one-   N-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}hexyl)guanidine,    dihydrochloride-   4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}but-2-enylamine-   4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}but-2-enylamine,    oxalate-   N-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)-N-isobutyrylguanidine-   3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}allylamine-   cis-2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}cyclopropylmethylamine-   N-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}allyl)guanidine,    trihydrochloride-   2-[(azetidin-3-ylmethoxy)(3-bromophenyl)methyl]-1H-benzimidazole-   2-[(3-bromophenyl)(1-methylazetidin-3-ylmethoxy)methyl]-1H-benzimidazole-   2-[(2,6-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[(2-fluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[(5-ethylsulfanyl-2-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[(azetidin-3-ylmethoxy)(2-fluoro-5-trifluoromethoxyphenyl)methyl]-1H-benzimidazole,    oxalate-   2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylazetidin-3-ylmethoxy)methyl]-1H-benzimidazole,    oxalate-   2-[(3-ethylsulfanyl-2,6-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[(2,2-difluorobenzo[1,3]dioxol-5-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole-   2-[(piperidin-4-yloxy)thiophen-3-ylmethyl]-1H-benzimidazole-   2-[(1-methylpiperidin-4-yloxy)thiophen-3-ylmethyl]-1H-benzimidazole-   2-[(piperidin-4-yloxy)thiophen-2-ylmethyl]-1H-benzimidazole-   2-[(1-methylpiperidin-4-yloxy)thiophen-2-ylmethyl]-1H-benzimidazole

as well as their enantiomers, diastereomers, mixtures thereof andpharmaceutically acceptable salts, free forms, tautomers, hydrates andsolvates.

The compounds of formula (I) can comprise one or more asymmetric carbonatoms. They can therefore exist in the form of enantiomers ordiastereoisomers. These enantiomers and diastereoisomers, as well astheir mixtures, including racemic mixtures, form part of the invention.

The compounds of the invention may also comprise tautomeric forms whichare all encompassed by the present invention. In particular, in formula(I), the group:

may have tautomeric forms such as when HetAr is a phenyl and X is N,leading to 1H-benzimidazole which is a tautomer of 3H-benzimidazole. Arepresentative example is illustrated below:

The compounds of formula (I) can be provided in the form of a free baseor in the form of addition salts with acids, which also form part of theinvention.

These salts are advantageously prepared with pharmaceutically acceptableacids, but salts with other acids, useful for example for thepurification or for the isolation of the compounds of formula (I), alsoform part of the invention.

As used herein, the term “patient” refers to a warm-blooded animal suchas a mammal, preferably a human or a human child, which is afflictedwith, or has the potential to be afflicted with one or more diseases andconditions described herein.

As used herein, a “therapeutically effective amount” refers to an amountof a compound of the present invention which is effective in reducing,eliminating, treating or controlling the symptoms of theherein-described diseases and conditions. The term “controlling” isintended to refer to all processes wherein there may be a slowing,interrupting, arresting, or stopping of the progression of the diseasesand conditions described herein, but does not necessarily indicate atotal elimination of all disease and condition symptoms, and is intendedto include prophylactic treatment and chronic use.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. The pharmaceutically acceptable saltsinclude the conventional non-toxic salts or the quaternary ammoniumsalts of the parent compound formed, for example, from non-toxicinorganic or organic acids. For example, such conventional non-toxicsalts include those derived from inorganic acids such as hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; andthe salts prepared from organic acids such as acetic, propanoic,succinic, tartaric, citric, methanesulfonic, benzenesulfonic,glucuronic, glutamic, benzoic, salicylic, toluenesulfonic, oxalic,fumaric, maleic, and the like. Further addition salts include ammoniumsalts such as tromethamine, meglumine, epolamine, etc., metal salts suchas sodium, potassium, calcium, zinc or magnesium. Hydrochloride andoxalate salts are preferred.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two. Generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17^(th) ed., Mack Publishing Company, Easton,Pa., 1985, p. 1418, the disclosure of which is hereby incorporated byreference.

The compounds of the general formula (I) having geometrical andstereomers are also a part of the invention.

According to a further object, the present invention is also concernedwith the process of preparation of the compounds of formula (I).

The compounds and process of the present invention may be prepared in anumber of ways well known to those skilled in the art. The compounds canbe synthesized, for example, by application or adaptation of the methodsdescribed below, or variations thereon as appreciated by the skilledartisan. The appropriate modifications and substitutions will be readilyapparent and well known or readily obtainable from the scientificliterature to those skilled in the art.

In particular, such methods can be found in R. C. Larock, ComprehensiveOrganic Transformations, VCH publishers, 1989.

It will be appreciated that the compounds of the present invention maycontain one or more asymmetrically substituted carbon atoms, and may beisolated in optically active or racemic forms. Thus, all chiral,diastereomeric, racemic forms and all geometric isomeric forms of astructure are intended, unless the specific stereochemistry or isomericform is specifically indicated. It is well known in the art how toprepare and isolate such optically active forms. For example, mixturesof stereomers may be separated by standard techniques including, but notlimited to, resolution of racemic forms, normal, reverse-phase, andchiral chromatography, preferential salt formation, recrystallization,and the like, or by chiral synthesis either from chiral startingmaterials or by deliberate synthesis of target chiral centers.

Compounds of the present invention may be prepared by a variety ofsynthetic routes. The reagents and starting materials are commerciallyavailable, or readily synthesized by well-known techniques by one ofordinary skill in the arts. All substituents, unless otherwiseindicated, are as previously defined.

In the reactions described hereinafter, it may be necessary to protectreactive functional groups, for example hydroxy, keto, amino, imino,thio or carboxy groups, where these are desired in the final product, toavoid their unwanted participation in the reactions. Conventionalprotecting groups may be used in accordance with standard practice, forexamples see T. W. Greene and P. G. M. Wuts in Protective Groups inOrganic Chemistry, John Wiley and Sons, 1991; J. F. W. McOmie inProtective Groups in Organic Chemistry, Plenum Press, 1973.

Some reactions may be carried out in the presence of a base. There is noparticular restriction on the nature of the base to be used in thisreaction, and any base conventionally used in reactions of this type mayequally be used here, provided that it has no adverse effect on otherparts of the molecule. Examples of suitable bases include: sodiumhydroxide, potassium carbonate, triethylamine, alkali metal hydrides,such as sodium hydride and potassium hydride; alkyllithium compounds,such as methyllithium and butyllithium; and alkali metal alkoxides, suchas sodium methoxide and sodium ethoxide.

Usually, reactions are carried out in a suitable solvent. A variety ofsolvents may be used, provided that it has no adverse effect on thereaction or on the reagents involved. Examples of suitable solventsinclude: hydrocarbons, which may be aromatic, aliphatic orcycloaliphatic hydrocarbons, such as hexane, cyclohexane,methylcyclohexane, toluene and xylene; amides, such asN,N-dimethylformamide; alcohols such as ethanol and methanol and ethers,such as diethyl ether, methyl tert-butyl ether, methyl cyclopentyl etherand tetrahydrofuran.

The reactions can take place over a wide range of temperatures. Ingeneral, we find it convenient to carry out the reaction at atemperature of from 0° C. to 150° C. (more preferably from about roomtemperature to 100° C.). The time required for the reaction may alsovary widely, depending on many factors, notably the reaction temperatureand the nature of the reagents. However, provided that the reaction iseffected under the preferred conditions outlined above, a period of from3 hours to 20 hours will usually suffice.

The compound thus prepared may be recovered from the reaction mixture byconventional means. For example, the compounds may be recovered bydistilling off the solvent from the reaction mixture or, if necessary,after distilling off the solvent from the reaction mixture, pouring theresidue into water followed by extraction with a water-immiscibleorganic solvent and distilling off the solvent from the extract.Additionally, the product can, if desired, be further purified byvarious well-known techniques, such as recrystallization,reprecipitation or the various chromatography techniques, notably columnchromatography or preparative thin layer chromatography.

The process of preparation of a compound of formula (I) of the inventionis another object of the present invention.

Compounds of formula (I) where A=O can be prepared by etherification ofcompound of formula (II):

in which X, HetAr and Ar are as defined in general formula (I)

with a compound of formula (III):

in which R, HET and B are as defined in general formula (I)

This etherification reaction can be performed in acidic medium(toluenesulfonic acid, methanesulfonic acid) in an inert solvent(toluene, dichlorobenzene, dichloroethane) at a temperature between roomtemperature and about 160° C.

Compounds of formula (II) can be prepared by condensing a benzothiazoleor a benzimidazole derivative with an aldehyde ArCHO, by condensing anorganometallic derivative ArMetal with an optionally substitutedbenzimidazole-2-carboxaldehyde or an optionally substitutedbenzothiazole-2-carboxaldehyde, or by condensing a hydroxy acidArCHOHCOOH with an optionally substituted ortho-phenylenediamine or anoptionally substituted 2-aminothiophenol or 2-aminophenol

Compounds of formula (I) wherein A=NH can be prepared by reduction ofcompound of formula (IV):

in which R, HET, B, X, HetAr and Ar are as defined in general formula(I)

This reduction can be performed by hydrogenation with dihydrogen ortransfer hydrogenation (formic acid, formic acid/triethylamine, ammoniumformate) in the presence of a catalyst (palladium on charcoal) in aninert solvent (methanol, ethanol, ethyl acetate) at a temperaturecomprised between room temperature and about 150° C.

Compounds of formula (IV) in which R, HET, B, X, HetAr and Ar are asdefined in general formula (I) can be prepared by condensing compound offormula (V):

in which X, HetAr and Ar are as defined in general formula (I)

with an amine

This condensation can be performed in the presence of an acid (titaniumtetraisopropoxide) in an inert solvent (tetrahydrofurane) at atemperature comprised between room temperature and reflux of the medium.

Compounds of formula (V) in which X, HetAr and Ar are as defined ingeneral formula (I) can be prepared by oxidizing compound of formula(II) in which X, HetAr and Ar are as defined in general formula (I).

This oxidation can be performed with an oxidizing agent (potassiumpermanganate, barium permanganate, manganese dioxide) in an inertsolvent (dioxane, acetonitrile) at a temperature comprised between roomtemperature and reflux of the medium.

Compounds of formula (I) where A=NH can be prepared by condensation ofcompound of formula (II):

in which X, HetAr and Ar are as defined in general formula (I)

with an amine

This condensation can be performed in the presence of a transition metalcatalyst such as dichloro(pentamethylcyclopentadienyl)iridium(III)dimer, in the presence of a base such as sodium hydrogenocarbonate in aninert solvent such as toluene at a temperature comprised between about80 and 150° C.

Alternatively, compounds of formula (I) in which A and X are NH can beprepared by condensing an organometallic reagent ArM onto a compound offormula (VI):

in which R, HET, B, HetAr and Ar are as defined in general formula (I)

This addition can be performed by adding a Grignard reagent onto animine in an inert solvent (tetrahydrofurane) at a temperature comprisedbetween room temperature and reflux of the medium.

Compounds of formula (VI) in which R, HET, B, HetAr and Ar are asdefined in general formula (I) can be prepared by condensing anoptionally substituted benzimidazole-2-carboxaldehyde or heteroarylfused imidazole-2-carboxaldehyde with an amine

This condensation can be performed in the presence of molecular sievesor other dehydrating agent in an inert solvent (ethanol) at atemperature comprised between 40° C. and the refluxing temperature. ADean Stark apparatus can also be used.

Alternatively, compounds of formula (I) in which A=O can be prepared byalkylation of compound of formula (VII):

in which HET, B, X, HetAr and Ar are as defined in general formula (I)

This alkylation can be performed by reductive method using acarbonylated compound and a reducing agent such as a borohydride, acyanoborohydride, a triacetoxyborohydride, hypophosphonous acid, formicacid, formic acid/triethylamine or hydrogen, a catalyst such aspalladium can be added for this transformation when hydrogen or hydrogendonnors are used.

Compounds of formula (VII) can be prepared by deprotection of compoundof formula (VIII):

in which HET, B, X, HetAr and Ar are as defined in general formula (I)and Prot is a protecting group of the nitrogen atom.

When Prot is a tert-butoxycarbonyl group, the transformation is usuallyperformed in acidic medium such a trifluoroacetic diluted withdichloromethane or in a solvent (ethyl acetate, ethanol, isopropanol)containing HCl. Preferably, this deprotection is performed at atemperature between 0° C. and the refluxing temperature of the medium.

Compounds of formula (VIII) in which HET, B, X, HetAr and Ar are asdefined in general formula (I) and Prot is a protecting group of thenitrogen atom can be prepared using the general methods described above.

Alternatively, compounds of formula (VIII) in which A=O and HET, B, X,HetAr and Ar are as defined in general formula (I) and Prot is aprotecting group of the nitrogen atom can be prepared by condensing anacid of formula (IX):

in which HET, B and Ar are as defined in general formula (I) and Prot isa protecting group of the nitrogen atom,

with an optionally substituted ortho-phenylenediamine or an optionallysubstituted 2-aminothiophenol.

This condensation can be performed by reacting the two compounds inacidic medium, or by first forming the amide bond with usual bondforming reagents, then dehydrating in acidic medium (acetic acid,hydrochloric acid) at a temperature comprised between room temperatureand reflux.

Acids of formula (IX) in which HET, B and Ar are as defined in generalformula (I) and Prot is a protecting group of the nitrogen atom can beprepared by hydrolysis of their esters. This hydrolysis can be performedin basic medium or in acidic medium at a temperature comprised between0° C. and reflux of the medium.

Esters of the acid of formula (IX) in which HET, B, X and Ar are asdefined in general formula (I) and Prot is a protecting group of thenitrogen atom can be prepared by condensing an ester of the acid (X)

with an alcohol

This condensation can be performed in the presence of a metal catalystsuch as rhodium acetate dimer in an inert solvent such a dichloromethaneor dichloroethane, at a temperature comprised between 0° C. and refluxof the medium.

Esters of the acid of formula (X) can be prepared from esters of an acidArCH2COOH with a diazo transfer reagent such as tosylazide in thepresence of a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene in aninert solvent such as acetonitrile at a temperature comprised between−20° C. and 40° C.

Furthermore, compounds of formula (I) can be prepared from compounds offormula (I) by group interconversion or group transformation. Suchreaction include, but are not limited to, reaction on aromatic orheteroaromatic groups such as halogen exchange reaction, Sonogashirareaction, Heck reaction, Suzuki reaction, sulfide condensation, triflatedisplacement with grignard reagents, copper catalysed ether formation,metal catalysed amine aromatic substitution, aromatic carbonylationreaction; reaction on reactive groups such as acylation,alcoxycarbonylation of nitrogen containing groups such as amines,amidines, guanidines; substitution of hydroxy with nucleophile(Mitsunobu reaction or activation and nucleophilic substitution);hydrogenation of unsaturation (alkenyl to alkyl, alkynyl to alkenyl,alkynyl to alkyl); Staudinger reduction of azido group.

The process of the invention may comprise the additional step ofisolating the desired compound of formula (I).

The starting products and/or reagents may be commercially available, ormay be readily prepared by the skilled person by applying or adaptingthe procedures disclosed in the experimental part below.

According to a still further object, the present invention is alsoconcerned with pharmaceutical compositions comprising a compound offormula (I) as defined above with a pharmaceutically acceptableexcipient.

The compounds of the invention are antagonists and/or inverse agonistsof H4 R. The pharmaceutical compositions and compounds of the inventionmay thus be useful for use in the treatment and/or prevention of adisease associated with H₄ dysfunction, such as inflammatory disorders.

Said disease includes adult respiratory distress syndrome, acuterespiratory distress syndrome, bronchitis, chronic bronchitis, chronicobstructive pulmonary disease, cystic fibrosis, asthma, emphysema,rhinitis, chronic sinusitis, allergy, allergy induced airway responses,allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial andseasonal rhinitis, conjunctivitis, nasal congestion, allergiccongestion; disorders of the genito-urinary tract such as female andmale sexual dysfunction, overactive bladder conditions, urinaryincontinence, bladder overactivity, benign prostate hyperplasia andlower urinary tract symptoms; dermatological diseases such as dermatitisand psoriasis and treatment of itchy skin; diseases of thecardiovascular system including thromboembolic diseases,atherosclerosis, myocardial infarction, angina pectoris, myocardialischaemia and arrhythmia, peripheral arterial occlusive diseases,pulmonary embolisms or deep venous thromboses, hypotension, pulmonaryhypertension, malignant hypertension, cardiac insufficiency, heart orkidney failure, stroke and renal dysfunction; diseases of thegastrointestinal tract including inflammatory bowel disease, Crohn'sdisease, ulcerative colitis; autoimmune diseases including rheumatoidarthritis, multiple sclerosis; cancer; pain; lymphatic diseases.

According to a further object, the present invention also concerns acombination of a compound of the invention with one or more therapeuticagent(s) selected from:

-   -   Histamine H₁, H₂ or H₃ receptor antagonists,    -   Leukotriene antagonists,    -   5-Lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating        protein (FLAP) antagonists    -   CX₁- and α₂-adrenoceptor agonist vasoconstrictor sympathomimetic        agents for decongestant use    -   Xanthines, such as theophylline and aminophylline    -   Non-steroidal antiinflammatories, such as sodium cromoglycate        and nedocromil sodium    -   Ketotifen    -   COX-1 inhibitors (NSAIDs) and COX-2 selective inhibito    -   Immunosuppressants    -   mucolytics or anti-tussive agents

More particularly, the present invention also concerns combinationscomprising a compound of formula (I) of the invention with a H1Rantagonist, such as cetirizine, desloratadine, bepotastine or doxepin.

According to a still further object, the present invention is alsoconcerned with a compound of formula (I) for the above conditions to beadministered to a patient in the need thereof.

According to a still further object, the present invention also concernsthe methods of treatment comprising administering an effective amount ofa compound of the invention for treating and/or preventing the aboveconditions or disorders.

The identification of those subjects who are in need of treatment ofherein-described diseases and conditions is well within the ability andknowledge of one skilled in the art. A clinician skilled in the art canreadily identify, by the use of clinical tests, physical examination andmedical/family history, those subjects who are in need of suchtreatment.

A therapeutically effective amount can be readily determined by theattending diagnostician, as one skilled in the art, by the use ofconventional techniques and by observing results obtained underanalogous circumstances. In determining the therapeutically effectiveamount, a number of factors are considered by the attendingdiagnostician, including, but not limited to: the species of subject;its size, age, and general health; the specific disease involved; thedegree of involvement or the severity of the disease; the response ofthe individual subject; the particular compound administered; the modeof administration; the bioavailability characteristic of the preparationadministered; the dose regimen selected; the use of concomitantmedication; and other relevant circumstances.

The amount of a compound of formula (I), which is required to achievethe desired biological effect, will vary depending upon a number offactors, including the dosage of the drug to be administered, thechemical characteristics (e.g. hydrophobicity) of the compoundsemployed, the potency of the compounds, the type of disease, thediseased state of the patient, and the route of administration.

In general terms, the compounds of this invention may be provided in anaqueous physiological buffer solution containing 0.1 to 10% w/v compoundfor parenteral administration. Typical dose ranges are from 1 μg/kg to0.1 g/kg of body weight per day; a preferred dose range is from 0.01mg/kg to 10 mg/kg of body weight per day. A preferred daily dose foradult humans includes 1, 5, 50, 100 and 200 mg, and an equivalent dosein a human child. The preferred dosage of drug to be administered islikely to depend on such variables as the type and extent of progressionof the disease or disorder, the overall health status of the particularpatient, the relative biological efficacy of the compound selected, andformulation of the compound excipient, and its route of administration.

The compounds of the present invention are capable of being administeredin unit dose forms, wherein the term “unit dose” means a single dosewhich is capable of being administered to a patient, and which can bereadily handled and packaged, remaining as a physically and chemicallystable unit dose comprising either the active compound itself, or as apharmaceutically acceptable composition, as described hereinafter. Assuch, typical daily dose ranges are from 0.01 to 10 mg/kg of bodyweight. By way of general guidance, unit doses for humans range from 0.1mg to 1000 mg per day. Preferably, the unit dose range is from 1 to 500mg administered one to four times a day, and even more preferably from 1mg to 300 mg, once a day. Compounds provided herein can be formulatedinto pharmaceutical compositions by admixture with one or morepharmaceutically acceptable excipients. Such compositions may beprepared for use in oral administration, particularly in the form oftablets or capsules; or parenteral administration, particularly in theform of liquid solutions, suspensions or emulsions; or intranasally,particularly in the form of powders, nasal drops, or aerosols; ordermally, for example, topically or via trans-dermal patches or ocularadministration, or intravaginal or intra-uterine administration,particularly in the form of pessaries or by rectal administration.

The compositions may conveniently be administered in unit dosage formand may be prepared by any of the methods well known in thepharmaceutical art, for example, as described in Remington: The Scienceand Practice of Pharmacy, 20^(th) ed.; Gennaro, A. R., Ed.; LippincottWilliams & Wilkins: Philadelphia, Pa., 2000. Pharmaceutically compatiblebinding agents and/or adjuvant materials can be included as part of thecomposition. Oral compositions will generally include an inert diluentcarrier or an edible carrier.

The tablets, pills, powders, capsules, troches and the like can containone or more of any of the following ingredients, or compounds of asimilar nature: a binder such as microcrystalline cellulose, or gumtragacanth; a diluent such as starch or lactose; a disintegrant such asstarch and cellulose derivatives; a lubricant such as magnesiumstearate; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, or methyl salicylate. Capsules can be in the form of a hardcapsule or soft capsule, which are generally made from gelatin blendsoptionally blended with plasticizers, as well as a starch capsule. Inaddition, dosage unit forms can contain various other materials thatmodify the physical form of the dosage unit, for example, coatings ofsugar, shellac, or enteric agents. Other oral dosage forms syrup orelixir may contain sweetening agents, preservatives, dyes, colorings,and flavorings. In addition, the active compounds may be incorporatedinto fast dissolve, modified-release or sustained-release preparationsand formulations, and wherein such sustained-release formulations arepreferably bi-modal.

Preferred formulations include pharmaceutical compositions in which acompound of the present invention is formulated for oral or parenteraladministration, or more preferably those in which a compound of thepresent invention is formulated as a tablet. Preferred tablets containlactose, cornstarch, magnesium silicate, croscarmellose sodium,povidone, magnesium stearate, or talc in any combination. It is also anaspect of the present disclosure that a compound of the presentinvention may be incorporated into a food product or a liquid.

Liquid preparations for administration include sterile aqueous ornon-aqueous solutions, suspensions, and emulsions. The liquidcompositions may also include binders, buffers, preservatives, chelatingagents, sweetening, flavoring and coloring agents, and the like.Non-aqueous solvents include alcohols, propylene glycol, polyethyleneglycol, acrylate copolymers, vegetable oils such as olive oil, andorganic esters such as ethyl oleate. Aqueous carriers include mixturesof alcohols and water, hydrogels, buffered media, and saline. Inparticular, biocompatible, biodegradable lactide polymer,lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylenecopolymers may be useful excipients to control the release of the activecompounds. Intravenous vehicles can include fluid and nutrientreplenishers, electrolyte replenishers, such as those based on Ringer'sdextrose, and the like. Other potentially useful parenteral deliverysystems for these active compounds include ethylene-vinyl acetatecopolymer particles, osmotic pumps, implantable infusion systems, andliposomes.

Alternative modes of administration include formulations for inhalation,which include such means as dry powder, aerosol, or drops. They may beaqueous solutions containing, for example, polyoxyethylene-9-laurylether, glycocholate and deoxycholate, or oily solutions foradministration in the form of nasal drops, or as a gel to be appliedintranasally. Formulations for buccal administration include, forexample, lozenges or pastilles and may also include a flavored base,such as sucrose or acacia, and other excipients such as glycocholate.Formulations suitable for rectal administration are preferably presentedas unit-dose suppositories, with a solid based carrier, such as cocoabutter, and may include a salicylate. Formulations for topicalapplication to the skin preferably take the form of an ointment, cream,lotion, paste, gel, spray, aerosol, or oil. Carriers which can be usedinclude petroleum jelly, lanolin, polyethylene glycols, alcohols, ortheir combinations. Formulations suitable for transdermal administrationcan be presented as discrete patches and can be lipophilic emulsions orbuffered, aqueous solutions, dissolved and/or dispersed in a polymer oran adhesive.

Alternative administrations include also solutions, ointments or otherformulations acceptable for ocular administration.

Other features of the invention will become apparent in the course ofthe following description of exemplary embodiments that are given forillustration of the invention and not intended to be limiting thereof.

EXAMPLES

Melting points are determinated on Büchi capillary melting pointapparatus.

Proton NMR spectra are recorded on a Bruker 250 MHz NMR instrument.Deuterochloroform is used as solvent unless otherwise stated. Thechemicals shifts δ are expressed in ppm. The following abbreviations areused to denote signal patterns: s=singlet, d=doublet, t=triplet,q=quadruplet, m=multiplet, ms=massif. The coupling contents areexpressed in Hz. The spectra recorded are consistent with the proposedstructures.

TLC are performed on 0.25 mm silica gel F254 plates.

Example 1 2-[(1-methylpiperidin-4-yloxy)phenylmethyl]benzothiazole 1A

A mixture of benzothiazol-2-ylphenylmethanol (0.36 g),4-hydroxy-1-methylpiperidine (0.17 g) and para-toluenesulfonic acid(0.57 g) in toluene (22 mL) is heated overnight in a Dean-Starkapparatus. The mixture is cooled back to room temperature and pouredinto water, alcalinised with 1N sodium hydroxide and extracted twicewith ethyl acetate. Pooled organic extracts are washed with brine, driedover magnesium sulfate and concentrated. The residue is purified bycolumn chromatography over silica gel (gradient dichloromethane/methanolfrom 98/2 to 90/10) to give2-[(1-methylpiperidin-4-yloxy)phenylmethyl]benzothiazole melting at 115°C.

1B

A solution of benzothiazole (1.35 g) in tetrahydrofurane (10 mL) in adried round bottom balloon is cooled at −70° C. A solution of butyllithium (4.1 mL) is added and the mixture stirred for 15 minutes.Benzaldehyde (1.03 mL) diluted with tetrahydrofurane (10 mL) is thenadded. The mixture is stirred at −70° C. for 1 h, allowed to warm to−20° C. and quenched with saturated aqueous ammonium chloride solution.The mixture is extracted with ethyl acetate. Organic extracts arepooled, dried over magnesium sulfate and concentrated under reducedpressure. Trituration of the residue with diisopropyl oxide affordsbenzothiazol-2-ylphenylmethanol.

TLC (heptane/ethyl acetate 1/1) Rf=0.57

Further examples can be prepared according to the described generalmethods:

Example Product General methods Melting point 22-[(1-methylpyrrolidin-3-yloxy)phenylmethyl]- 1A, 1B 120° C.benzothiazole, oxalate 3 2-[(4-fluorophenyl)(1-methylpiperidin-4- 1A, 1B192° C. yloxy)methyl]benzothiazole, oxalate 42-[(4-chlorophenyl)(1-methylpiperidin-4- 1A, 1B 147-148° C.yloxy)methyl]benzothiazole, oxalate 52-[(3-fluorophenyl)(1-methylpiperidin-4- 1A, 1B 167-170° C.yloxymethyl]benzothiazole, oxalate 62-[(2-fluorophenyl)(1-methylpiperidin-4- 1A, 1B 178-179° C.yloxy)methyl]benzothiazole, oxalate 7 2-[(1-methylpiperidin-4-yloxy)-p-1A, 1B 177° C. tolylmethyl]benzothiazole, oxalate 82-[(1-methylpiperidin-4-yloxy)(m- 1A, 1B 177° C.tolyl)methyl]benzothiazole, oxalate 102-[(2,3-dihydrobenzo[1,4]dioxin-6-yl)(1- 1A, 1B 71° C.methylpiperidin-4-yloxy)methyl]benzothiazole, hydrochloride 112-[(3-methoxyphenyl)(1-methylpiperidin-4- 1A, 1B 182° C.yloxy)methyl]benzothiazole, hydrochloride 122-[(2,4-difluorophenyl)(1-methylpiperidin-4- 1A, 1B 182° C.yloxy)methyl]benzothiazole, dioxalate 142-[(4-methoxyphenyl)(1-methylpiperidin-4- 1A, 1B 72° C.yloxy)methyl]benzothiazole, dihydrochloride 152-[(3,5-difluorophenyl)(1-methylpiperidin-4- 1A, 1B 165° C.yloxy)methyl]benzothiazole, oxalate

Following compounds are prepared using general methods described inExample 1:

Example Product  9 (benzothiazol-2-yl-phenylmethyl)(1-methylpiperidin-4-yl)amine ¹H NMR: 8.00 (d, 1H), 7.90 (d, 1H), 7.55-7.35 (m, 2H), 7.32 (d,1H), 7.10 (d, 1H), 6.98 (d, 1H), 6.17 (s, 1H), 3.80-3.65 (m, 1H), 2.80-2.65 (m, 2H), 2.29 (s, 3H),), 2.28-2.15 (m, 2H), 2.10-1.80 (m, 4H) 132-[(1-methylpiperidin-4-yloxy)thiophen-2-ylmethyl]benzothiazole ¹H NMR:7.95 (d, 1H), 7.84 (d, 1H), 7.52 (m, 2H), 7.50-7.25 (m, 5H), 5.44 (s,1H), 3.88-3.75 (m, 2H), 3.65-3.50 (m, 1H), 2.24 (s, 3H),), 2.15- 1.85(m, 4H), 1.65-1.35 (m, 2H) 232-[(1-methylpiperidin-4-yloxy)(3-trifluoromethoxy-phenyl)methyl]benzothiazole, oxalate ¹H NMR (DMSO-d⁶): 7.99 (d, 1H),7.87 (d, 1H), 7.55-7.35 (m, 5H), 7.27-7.15 (m, 1H), 6.11 (s, 1H),3.95-3.80 (m, 1H), 3.50-3.00 (m, 6H), 2.79 (s, 3H),), 2.20-1.70 (m, 4H),

Example 16 16A

A mixture of (benzothiazol-2-yl)(thien-3-yl)methanol (0.247 g),4-hydroxy-1-methylpiperidine (0.115 g) and para-toluenesulfonic acid(0.27 g) in dichloroethane (20 mL) is heated for 4H in a Dean-Starkapparatus. The mixture is concentrated under reduced pressure and theresidue taken up in ethyl acetate. The organic phase is washed withwater, dried over magnesium sulfate and concentrated. The residue ispurified by column chromatography over silica gel (gradientdichloromethane/methanol from 100/0 to 95/5). Salification with oxalicacid in acetone gives-[(1-methylpiperidin-4-yloxy)thiophen-3-ylmethyl]benzothiazole oxalatemelting at 174° C.

16B

(benzothiazol-2-yl)(thien-3-yl)methanol is prepared according to generalmethod 1B.

Example 21 21A

A solution of[(benzothiazol-2-yl)(m-tolyl)methylene](1-methylpiperidin-4-yl)amine(0.45 g) in methanol (30 mL) containing 10% palladium on charcoal (0.1g) is stirred under dihydrogene (1 atm) at room temperature for 3 h. Thesuspension is filtered over clarcel and concentrated under reducedpressure. The residue is dissolved in acetone (2 mL) and mixed with asolution of oxalic acid (76 mg) in acetone (2 mL). A precipitate formswhich is filtered, rinsed with acetonitrile and diethyl ether and driedunder vacuum to afford[(benzothiazol-2-yl)(m-tolyl)methyl](1-methylpiperidin-4-yl)aminedioxalate melting at 127° C.

21B

To a solution of (benzothiazol-2-yl)(m-tolyl)methanone (1.06 g) and4-amino-1-methylpiperidine (0.456 g) in tetrahydrofurane (4 mL) is addedtitanium tetraisopropoxide (1.42 g). The mixture is stirred at roomtemperature for 1 h, then polymethyl hydrosiloxane (1.2 mL) is added.The mixture is stirred for one day at room temperature, diluted withethyl acetate (50 mL), hydolysed with 3N sodium hydroxide (30 mL). Theorganic phase is separated by decantation, washed with water, dried overmagnesium sulfate and concentrated in vacuo. The residue is crystallisedby trituration in diisopropyl oxide. A second crop can be obtained formthe mother liquor by chromatography over silica gel (gradientdichloromethane/methanol from 98/2 to 95/5) to give[(benzothiazol-2-yl)(m-tolyl)methylene](1-methylpiperidin-4-yl)aminemeting at 125° C.

21C

To a solution of (benzothiazol-2-yl)(m-tolyl)methanol (2.41 g) indioxane (30 mL) is added manganese dioxide (1.2 molar equivalent). Themixture is stirred overnight at room temperature, then filtered over aclarcel pad. The filtrate is concentrated under reduced pressure. Theresidue is triturated in heptane and diisopropyl oxide to give(benzothiazol-2-yl)(m-tolyl)methanone

21D

(benzothiazol-2-yl)(m-tolyl)methanol can be obtained as described inExample 1B.

Further examples can be prepared according to the described generalmethods:

General Melting Example Product methods point 172-[(1-methylpiperidin-4-yloxy)naphthalen-1- 1A, 1B 106.5° C.  ylmethyl]benzothiazole 18 2-[(1-methylpiperidin-4-yloxy)naphthalen-2-1A, 1B 198° C. ylmethyl]benzothiazole, dihydrochloride 192-[(1-methylpiperidin-4-yloxy)(5-methylthiophen-2- 16A, 1B 174° C.yl)methyl]benzothiazole, oxalate 202-[benzo[1,3]dioxol-5-yl(1-methylpiperidin-4- 1A, 1B 110° C.yloxy)methyl]benzothiazole, dihydrochloride 242-[(1-methylpiperidin-4-yloxy)(4- 1A, 1B 155° C.trifluoromethoxyphenyl)methyl]benzothiazole, oxalate 25[benzothiazol-2-yl(3-methoxyphenyl)methyl](1- 21A, 21B, 160° C.methylpiperidin-4-yl)amine, dioxalate 21C, 1B 272-[(3-bromo-phenyl)(1-methylpiperidin-4- 1A, 1B  99° C.yloxy)methyl]benzothiazole 28 2-[(1-methylpiperidin-4-yloxy)(3-phenoxy-1A, 1B  92° C. phenyl)methyl]benzothiazole, oxalate 295-methyl-2-[(1-methylpiperidin-4- 1A, 1B 175° C.yloxy)phenylmethyl]benzothiazole, oxalate 302-[(1-methylpiperidin-4-yloxy)phenylmethyl]-1H- 1A, 1B 110° C.benzimidazole 31 2-[(1-methylpiperidin-4-yloxy)(3- 1A, 1B  61° C.trifluoromethylphenyl)methyl]benzothiazole, hydrochloride 342-[(4-fluoro-3-methylphenyl)(1-methylpiperidin-4- 1A, 1B 120° C.yloxy)methyl]benzothiazole, oxalate 35[benzothiazol-2-yl(4-fluoro-3-methyl-phenyl)methyl](1- 1A, 1B 160° C.methylpiperidin-4-yl)amine, dioxalate 36(benzothiazol-2-yl-p-tolylmethyl)(1-methylpiperidin-4- 1A, 1B 110° C.yl)amine, oxalate 38 2-[(3-fluoro-5-methylphenyl)(1-methylpiperidin-4-1A, 1B 170° C. yloxy)methyl]benzothiazole, oxalate

Example 26

To a solution of2-[(3-allyloxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazoleexample 22 (250 mg) in ethanol (10 mL) is added 10% palladium oncharcoal (25 mg). The mixture is stirred overnight under dihydrogene (1atm) at room temperature, then filtrated over a clarcel pad. Thefiltrate is concentrated under reduced pressure to give the crude basewhich is converted to2-[(1-methylpiperidin-4-yloxy)(3-propoxy-phenyl)methyl]benzothiazole,dihydrochloride melting at 59° C.

Following compounds are prepared using general methods described inexample 1:

Example Product 335-fluoro-2-[(1-methylpiperidin-4-yloxy)phenylmethyl]benzo- thiazole ¹HNMR: 7.80 (dd, 1H), 7.65 (dd, 1H), 7.58-7.68 (m, 2H), 7.45-7.28 (m, 3H),7.14 (dt, 1H), 5.89 (s, 1H), 3.80-3.60 (m, 1H), 2.90-2.72 (m, 2H), 2.38(s, 3H), 2.15-1.70 (m, 6H)

Example 37 37A

Reduction of[(benzofuran-2-yl)(benzothiazol-2-yl)methylene](1-methylpiperidin-4-yl)amineas described in example 21A affords[(benzofuran-2-yl)(benzothiazol-2-yl)methyl](1-methylpiperidin-4-yl)amineoxalate melting at 125° C.

37B

To a solution of (benzofuran-2-yl)(benzothiazol-2-yl)methanone (1.4 g)and 4-amino-1-methylpiperidine (0.57 g) in tetrahydrofurane (8 mL) isadded dropwise titanium tetraisopropoxide (1.78 g). The suspension isstirred for 24 h at room temperature, diluted with ethyl acetate and 1Nsodium hydroxide. The precipitate is filtered over a clarcel pad andrinsed with ethyl acetate. The pooled filtrates are washed withsaturated sodium chloride solution, dried and concentrated under reducedpressure. The residue is purified over silica gel (gradientdichloromethane/methanol from 100/0 to 90/10) to afford[(benzofuran-2-yl)(benzothiazol-2-yl)methylene](1-methylpiperidin-4-yl)amine.

37C

(benzofuran-2-yl)(benzothiazol-2-yl)methanone can be prepared asdescribed in example 21C.

37D

(benzofuran-2-yl)(benzothiazol-2-yl)methanone can be prepared asdescribed in example 1B.

Further examples can be prepared according to the described generalmethods:

General Melting Example Product methods point 39[(1H-benzimidazol-2-yl)phenylmethyl](1- 21A, 37B, 133° C.methylpiperidin-4-yl)amine 21C, 1B 402-[(3-fluoro-5-methoxyphenyl)(1-methylpiperidin-4- 1A, 1B 145° C.yloxy)methyl]benzothiazole, oxalate 412-[(3-iodophenyl)(1-methylpiperidin-4- 1A, 1B 165-170° C.yloxy)methyl]benzothiazole, oxalate

Example 42[benzothiazol-2-yl(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amine42A

Hydrogenation of[benzothiazol-2-yl(3-propoxyphenyl)methylene](1-methylpiperidin-4-yl)amineas described in example 21A gives[benzothiazol-2-yl(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)aminemelting at 90° C.

42B

Condensation of benzothiazol-2-yl(3-propoxyphenyl)methanone with4-amino-1-methylpiperidine as described in example 37B gives[benzothiazol-2-yl(3-propoxyphenyl)methylene](1-methylpiperidin-4-yl)amine.

42C

A mixture benzothiazol-2-yl(3-propoxyphenyl)methanol (1 g) and bariumpermanganate (0.95 g) in acetonitrile 15 mL) is refluxed for 30 minutes.The mixture is filtered over a clarcel pad, concentrated under reducedpressure and purified by column chromatography over silica gel (eluantheptane/ethyl acetate: 4/1) to givebenzothiazol-2-yl(3-propoxyphenyl)methanone as a white crystallinesolid.

42D

Benzothiazol-2-yl(3-propoxyphenyl)methanol can be prepared as describedin example 1B.

Further examples can be prepared according to the described generalmethods:

General Melting Example Product methods point 43[benzothiazol-2-yl(3-fluoro-5-methoxyphenyl)methyl](1- 21A, 37B, 157° C.methylpiperidin-4-yl)amine, oxalate 21C, 1B 44[benzothiazol-2-yl(3-fluoro-5-methylphenyl)methyl](1- 21A, 37B, 102° C.methylpiperidin-4-yl)amine 21C, 1B 452-[(3-benzyloxyphenyl)(1-methylpiperidin-4- 1A, 1B 52° C.yloxy)methyl]benzothiazole, oxalate 462-[benzofuran-5-yl(1-methylpiperidin-4- 1A, 1B 153° C.yloxy)methyl]benzothiazole, oxalate 472-[(3-ethoxyphenyl)(1-methylpiperidin-4- 1A, 1B 84° C.yloxy)methyl]benzothiazole, oxalate 48[benzothiazol-2-yl(3-iodophenyl)methyl](1- 21A, 37B, 188-195° C.methylpiperidin-4-yl)amine, oxalate 21C, 1B 492-[(1-methylpiperidin-4-yloxy)(3-propoxyphenyl)methyl]- 1A, 1B 135° C.1H-benzimidazole 50 [(1H-benzimidazol-2-yl)(3-propoxyphenyl)methyl](1-21A, 37B, 143° C. methylpiperidin-4-yl)amine 21C, 1B 512-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H- 1A, 1B 173.5° C.benzimidazole 52 (benzothiazol-2-ylpyridin-3-ylmethyl)(1- 21A, 37B, 109°C. methylpiperidin-4-yl)amine 42C, 1B

53

A mixture of2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole (200mg), phenylboronic acid (70 mg), palladium acetate (4.8 mg) and1,1-bis(diphenylphosphino)ferrocene is placed in a round-bottom flaskand purged with argon. A 1M aqueous degassed solution of potassiumcarbonate (1.51 mL) and degassed tetrahydrofuran (2 mL) are introduced.The mixture is heated at 95° C. for 30 min, cooled back to roomtemperature and filtered over a celite pad. The cake is rinsed withethyl acetate and water. The pooled phases are decanted. The organicphase is dried over magnesium sulfate and concentrated. The residue ispurified by column chromatography (gradient dichloromethane/methanolfrom 98/2 to 90/10) to give the crude base which is then converted tothe oxalate in acetone to give2-[biphenyl-3-yl(1-methylpiperidin-4-yloxy)methyl]benzothiazole, oxalateas a beige amorphous solid.

¹H NMR (DMSO-d⁶): 8.05 (d, 1H), 7.91 (d, 1H), 7.77 (s, 1H), 7.68-7.58(m, 3H), 7.55-7.30 (m, 7H), 6.20 (s, 1H), 3.90-3.78 (m, 1H), 3.32-2.90(m, 4H), 2.67 (s, 3H), 2.20-1.70 (m, 4H)

Following compounds are prepared analogously:

Example Product 54{3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxymethyl]biphenyl-3-yl}methanol,oxalate ¹H NMR (DMSO-d⁶): 8.02 (d, 1H), 7.87 (d, 1H), 7.72 (s, 1H),7.62-7.35 (m, 8H), 7.27 (d, 1H), 6.13 (s, 1H), 4.51 (s, 2H), 3.92-3.80(m, 1H), 3.40-2.90 (m, 4H), 2.70 (s, 3H), 2.25-1.70 (m, 4H) 632-[(1-methylpiperidin-4-yloxy)(3-pyridin-3-ylphenyl)methyl]benzothiazole,oxalate ¹H NMR (DMSO-d⁶): 8.86 (d, 1H), 8.57 (dd, 1H), 8.09-8.00 (m,2H), 7.92 (d, 1H), 7.84 (s, 1H), 7.73-7.63 (m, 1H), 7.58-7.37 (m, 5H),6.21 (s, 1H), 3.92-3.78 (m, 1H), 3.40-2.95 (m, 4H), 2.70 (s, 3H),2.25-1.75 (m, 4H) 793′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-ylamine,oxalate ¹H NMR (DMSO-d⁶): 8.07 (d, 1H), 7.91 (d, 1H), 7.66 (s, 1H),7.53-7.37 (m, 5H), 7.07 (t, 1H), 6.78 (s, 1H), 6.71 (d, 1H), 6.54 (d,1H), 6.18 (s, 1H), 4.20-3.70 (m, 5H), 3.42-2.95 (m, 4H), 2.70 (s, 3H),2.25-1.75 (m, 4H) 812-[biphenyl-3-yl(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole ¹HNMR: 12.38 (sl, 1H), 7.78 (s, 1H), 7.65-7.40 (m, 10H), 7.15-7.05 (m,2H), 5.91 (s, 1H), 3.50-3.35 (m, 1H), 2.68-2.50 (m, 2H), 2.10 (s, 3H),2.05-1.84 (m, 4H), 1.70-1.50 (m, 2H) 86{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-yl}methanol ¹H NMR (DMSO-d⁶): 12.37 (sl, 1H), 7.77 (s, 1H), 7.62-7.35(m, 8H), 7.28 (d, 1H), 7.15-7.02 (m, 2H), 5.92 (s, 1H), 5.22 (t, 1H),4.53 (d, 2H), 3.48-3.32 (m, 1H), 2.68-2.50 (m, 2H), 2.08 (s, 3H),2.00-1.78 (m, 4H), 1.69-1.48 (m, 2H) 873′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-ylamine¹H NMR: 9.57 (sl, 1H), 7.82-8.68 (m, 1H), 7.67 (s, 1H), 7.55-7.35 (m,4H), 7.30-7.15 (m, 3H), 6.94 (d, 1H), 6.85 (s, 1H), 6.67 (d, 1H), 5.92(s, 1H), 3.85-3.50 (m, 3H), 2.80-2.75 (m, 2H), 2.27 (s, 3H), 2.25-1.65(m, 6H) 892-[(1-methylpiperidin-4-yloxy)(3-pyridin-3-ylphenyl)methyl]-1H-benzimidazole¹H NMR: 9.62 (sl, 1H), 8.80 (d, 1H), 8.58 (dd, 1H), 7.83 (d, 1H),7.80-7.65 (m, 2H), 7.55-7.20 (m, 7H), 5.96 (s, 1H), 3.70-3.55 (m, 1H),2.85-2.70 (m, 2H), 2.30 (s, 3H), 2.25-1.65 (m, 6H) 962-[(2′-methoxybiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole¹H NMR: 8.02 (d, 1H), 7.88 (d, 1H), 7.74 (s, 1H), 7.55-7.25 (m, 7H),7.08-6.95 (m, 2H), 5.99 (s, 1H), 3.77 (s, 3H), 3.75-3.65 (m, 1H),2.82-2.68 (m, 2H), 2.29 (s, 3H), 2.29-2.15 (m, 2H), 2.10-1.80 (m, 4H) 972-[(1-methylpiperidin-4-yloxy)(3′-nitrobiphenyl-3-yl)methyl]benzothiazole¹H NMR: 8.45 (d, 1H), 8.22 (d, 1H), 7.99 (d, 1H), 7.95-7.85 (m, 2H),7.80 (s, 1H), 7.65-7.35 (m, 6H), 6.00 (s, 1H), 3.80-3.65 (m, 1H),2.88-2.70 (m, 2H), 2.42-2.25 (m, 2H), 2.34 (s, 3H), 2.10-1.70 (m, 4H) 992-[(3′-methoxybiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole¹H NMR: 7.98 (d, 1H), 7.86 (d, 1H), 7.74 (s, 1H), 7.68-7.30 (m, 6H),7.17 (d, 1H), 7.10 (d, 1H), 6.92 (d, 1H), 5.96 (s, 1H), 3.92-3.78 (m,1H), 3.86 (s, 3H), 3.05-2.85 (m, 2H), 2.85-2.55 (m, 2H), 2.50 (s, 3H),2.35-2.12 (m, 2H), 2.12-1.85 (m, 2H) 100 2-[(4′-methoxybiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole,oxalate ¹H NMR: 8.06 (d, 1H), 7.91 (d, 1H), 7.71 (s, 1H), 7.50-7.30 (m,7H), 7.02 (d, 2H), 6.18 (s, 1H), 3.92-3.78 (m, 1H), 3.77 (s, 3H),3.45-2.90 (m, 4H), 2.70 (s, 3H), 2.12-1.72 (m, 4H) 128 2-[(1-methylpiperidin-4-yloxy)(3′-methylsulfanylbiphenyl-3-yl)methyl]benzothiazole, oxalate ¹H NMR (DMSO d⁶): 8.07 (d, 1H), 7.92(d, 1H), 7.78 (s, 1H), 7.62 (sl, 1H), 7.55-7.32 (m, 7H), 7.27 (sl, 1H),6.20 (s, 1H), 3.45-3.30 (m, 1H), 3.30-2.82 (m, 4H), 2.67 (s, 3H), 2.47(s, 3H), 2.25-1.75 (m, 4H) 133 2-[(3′,4′-dichlorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole¹H NMR: 7.98 (d, 1H), 7.88 (d, 1H), 7.70 (s, 1H), 7.66 (d, 1H),7.52-7.35 (m, 7H), 5.97 (s, 1H), 3.82-3.68 (m, 1H), 2.95-2.78 (m, 2H),2.55-2.40 (m, 2H), 2.40 (s, 3H), 2.20-1.80 (m, 4H) 136 2-[(4′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole¹H NMR: 7.98 (d, 1H), 7.86 (d, 1H), 7.71 (s, 1H), 7.68-7.30 (m, 7H),7.15 (d, 1H), 7.10 (d, 1H), 5.98 (s, 1H), 3.80-3.63 (m, 1H), 2.88-2.72(m, 2H), 2.42-2.25 (m, 2H), 2.34 (s, 3H), 2.15-1.75 (m, 4H) 137 2-[(2′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole¹H NMR: 7.99 (d, 1H), 7.88 (d, 1H), 7.75 (s, 1H), 7.50-7.10 (m, 9H),5.98 (s, 1H), 3.82-3.75 (m, 1H), 2.88-2.70 (m, 2H), 2.33 (s 3H),2.40-2.20 (m, 2H), 2.12-1.85 (m, 4H)

72 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole72A

A mixture of 1H-benzimidazol-2-yl(3-bromophenyl)methanol (12.9 g),4-hydroxy-1-methylpiperidine (4.86 g) and para-toluenesulfonic acid (24g) in chlorobenzene (60 mL) and N-methylpyrrolidone (6 mL) is heatedunder reflux for 120 h in a Dean Stark apparatus. Solvent is removed byevaporation. To the residue is added water which is made alcaline byaddition of sodium hydroxide solution, then extracted with ethylacetate. The pooled organic extracts are washed with water, treated withactivated charcoal, dried over magnesium sulfate and concentrated underreduced pressure. The residue is triturated in diethyl ether to give2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole.

72B

A mixture of (3-bromophenyl)hydroxyacetic acid (20 g) andortho-phenylenediamine (9.36 g) in 5N aqueous hydrochloric solution (100mL) is heated under reflux for 4 h and cooled back to room temperature.The precipitate is separated by filtration, rinsed with acetonitrile anddried under vacuum with phosphorus pentoxide et give1H-benzimidazol-2-yl(3-bromophenyl)methanol as a white crystalline solidused without further purification.

72C

To a solution of 3-bromobenzaldehyde (18.5 g) in tetrahydrofuran (400mL) is added trimethylsilylcyanide (10.9 g). Two drops of a 1M solutionof tetrabutylammonium fluoride in tetrahydrofuran are added to thereaction mixture (a small exotherm is observed). After one hour at roomtemperature, solvent and volatiles are removed under reduced pressure.To the residual oil is added 6N aqueous hydrochloric acid (100 mL). Theround-bottom flask is equipped with a Dean-Stark apparatus and thereaction mixture is heated to reflux for 3 hours while removingsilanols.

The reaction mixture is cooled to 0° C. and a 10N sodium hydroxidesolution is added dropwise to reach pH 1. The aqueous phase is extractedwith ethyl acetate. The pooled organic phases are washed with brine;dried on magnesium sulphate and concentrated to dryness under reducedpressure. The residual solid is re-crystallized from hot toluene to give(3-bromophenyl)hydroxyacetic acid.

¹H NMR (DMSO-d⁶): 7.57 (t, 1H), (d, 1H), 7.45 (dt, 1H), 7.38 (s, 1H),7.28 (t, 1H), 5.03 (s, 1H).

Following compounds are prepared using general methods 21A and 21B:

Example Product 64[(1H-benzimidazol-2-yl)(3-bromophenyl)methyl](1-methyl-piperidin-4-yl)amine ¹H NMR: 9.60 (sl, 1H), 7.75 (sl, 1H), 7.65 (s, 1H),7.50-7.32 (m, 3H), 7.30-7.15 (m, 3H), 5.84 (s, 1H), 3.62-3.58 (m, 1H),2.85-2.68 (m, 2H), 2.28 (s, 3H), 2.25-1.65 (m, 7H)

Example 56[benzothiazol-2-yl(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amineenantiomer A

A solution of racemic[benzothiazol-2-yl(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amine(10 mg/mL) in a mixture of heptane/isopropanol (80/20) containingdiethylamine (0.1%) is injected (20×100 μL) onto an analytical ChiralpakAD-H, 250×4.6 mm column. Elution is performed with a mixture ofheptane/isopropanol (80/20) containing diethylamine (0.1%) at a flow of1 mL/min. Products are detected at 220 nm.

The first enantiomer has a retention time of 6.7 min.

Collection affords[benzothiazol-2-yl(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amineenantiomer A with a chromatographic enantiomeric purity of 92.6%.

Example 57[benzothiazol-2-yl(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amineenantiomer B

The second enantiomer has a retention time of 8.2 min.

Collection affords[benzothiazol-2-yl(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amineenantiomer B with a chromatographic enantiomeric purity of 98.8%.

Example 59[(1H-benzimidazol-2-yl)(3-trifluoromethylphenyl)methyl](1-methylpiperidin-4-yl)amine59A

To a solution of(1H-benzimidazol-2-ylmethylene)(1-methylpiperidin-4-yl)amine (70 mg) intetrahydrofurane (3 mL) is added a 1.5M solution of3-trifluoromethylphenylmagnesium bromide in tetrahydrofurane (0.77 mL)at room temperature. The mixture is then stirred at 40° C. for 1 h,hydrolyzed with water and extracted with ethyl acetate. The pooledorganic extracts are washed with brine, dried over magnesium sulfate andconcentrated under reduced pressure. The residue is purified by columnchromatography (gradient dichloromethane/methanol/ammonia from 95/5/0.5to 90/10/0.5) to give[(1H-benzimidazol-2-yl)(3-trifluoromethylphenyl)methyl](1-methylpiperidin-4-yl)amineas a yellow solid melting at 90° C.

59B

1H-Benzimidazole-2-carboxaldehyde (781 mg, can be prepared according toFegy, K. Angewandte Chemie Int Ed, 1998, vol. 37, 1270-1273),4-amino-1-methylpiperidine (781 mg) and 4 Å molecular sieves (15 g) inethanol (100 mL) are heated under reflux for 4 h. The mixture is thenfiltered and the filtrate concentrated under reduced pressure to yield(1H-benzimidazol-2-ylmethylene)(1-methylpiperidin-4-yl)amine as a beigesolid.

62

To a solution of2-[(3-allyloxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole(example 22) (2.35 g) in tetrahydrofurane (40 mL) is addedtetrakistriphenylphosphinepalladium (0.344 g). The mixture is stirredfor 5 min at room temperature, then sodium borohydride (0.576 g) isadded. The mixture is stirred for 20 h at room temperature, filteredover a clarcel pad. The pad is rinsed with ethyl acetate. Pooled organicphases are washed with aqueous ammonium chloride solution, then sodiumhydrogenocarbonate, dried over magnesium sulfate and concentrated underreduced pressure. The residue is purified by three columnchromatographies over silica gel (twice gradient heptane/ethyl acetatefrom 95/5 to 80/20, third eluant heptane/dichloromethane 5/1). Pooledfractions are concentrated under reduced pressure. The residue isdissolved in methanol, refluxed for 5 h and concentrated under reducedpressure. The residue is purified by column chromatography (gradientdichloromethane/methanol/ammonia from 100/0 to 90/10/1) to give3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenol as a beigesolid melting at 201° C.

* in the case of ketone-containing substituents, it is judicious toprotect the carbonyl function (as an acetal for example) prior to theGrignard preparation

Example 91 91A

A mixture of 4-amino-1-methylpiperidine (0.23 g),benzothiazol-2-yl(3-butoxyphenyl)methanol (0.63 g), sodiumhydrogenocarbonate (2 mg) anddichloro(pentamethylcyclopentadienyl)iridium(III) dimer (8 mg) intoluene (3 mL) is heated in an autoclave at 110-120° C. for 66 hours.The mixture is purified by chromatography over silica gel (eluantdichloromethane/methanol: 98/2) to give the crude base, which istransformed to the oxalate in acetone to give[benzothiazol-2-yl(3-butoxyphenyl)methyl](1-methylpiperidin-4-yl)amineoxalate melting at 176° C.

91B

Benzothiazol-2-yl(3-butoxyphenyl)methanol can be obtained as describedin example 1B.

Example 168 168A

2-[(1-methylpiperidin-4-yloxy)(3-pent-4-enyloxy-phenyl)methyl]benzothiazole,oxalate can be prepared as described in example 1A starting frombenzothiazol-2-yl(3-pent-4-enyloxy-phenyl)methanol to get an orangesolid melting at 75° C.

168B

Benzothiazol-2-yl(3-pent-4-enyloxy-phenyl)methanol can be prepared asfollows: to a 1M solution of 3-pent-4-enyloxy-phenylmagnesium bromide intetrahydrofurane (2.2 mL) diluted with the same solvent (6 mL) cooled at−50° C. is added benzothiazole-2-carboxaldehyde (326 mg). After stirringat −50° C. for 1 h, the mixture is allowed to warm at room temperature,then hydrolyzed with aqueous saturated ammonium chloride solution andextracted with ethyl acetate. The pooled organic extracts are dried overmagnesium sulfate and concentrated under reduced pressure. The residueis purified by column chromatography (gradient heptane/ethyl acetatefrom 4/1 to 2/1) to givebenzothiazol-2-yl(3-pent-4-enyloxy-phenyl)methanol as a yellow oil.

272 2-[(1-methylpyrrolidin-3-yloxy)phenyl-methyl]-1H-benzimidazole 272A

A mixture of (1H-benzimidazol-2-yl)phenylmethanol (611 mg) and1-methyl-3-pyrrolidinol (263 mg) in methanesulfonic acid (1.3 mL) isheated for 4 hours in a sealed tube at a temperature close to 140° C.The mixture is cooled back to room temperature, poured into water whichis then made alkaline with concentrated sodium hydroxide solution. Theaqueous phase is extracted with ethyl acetate. Pooled extracts are driedover magnesium sulfate, concentrated under reduced pressure. The residueis purified by column chromatography over silica gel (gradientdichloromethane/methanol from 100/0 to 90/10) to give2-[(1-methylpyrrolidin-3-yloxy)phenyl-methyl]-1H-benzimidazole meltingat 53° C.

For the other examples prepared according this general procedure, it canbe a good idea to rise the temperature progressively after having mixedthe different reagents and to observe when etherification occurs. Oncethe right temperature has been found, reaction is continued up toadequate conversion.

272B

To a solution of 1-pyrrolidin-1-ylmethyl-1H-benzimidazole (5 g) intetrahydrofurane (20 mL) cooled at a temperature close to −80° C., isadded a 2.5M solution of butyl lithium in hexanes (10 mL). The mixtureis stirred for 15 minutes. A solution of benzaldehyde (2.64 g) intetrahydrofurane (20 mL) is added. The mixture is stirred at atemperature close to −80° C. for 1 hour, then at a temperature close to−20° C. for 2 hours. The reaction is quenched by addition of saturatedammonium chloride. The mixture is extracted with ethyl acetate. Pooledextracts are washed with brine, dried over magnesium sulfate andconcentrated under reduced pressure. The residue is purified by columnchromatography over silica gel (gradient dichloromethane/methanol from100/0 to 90/10) to give (1H-benzimidazol-2-yl)phenylmethanol usedwithout further purification.

1-Pyrrolidin-1-ylmethyl-1H-benzimidazole can be prepared as described byKatritzky, Alan R.; Aslan, Diana C.; Leeming, Peter; Steel, Peter J.Tetrahedron: Asymmetry, 1997, 8, p. 1491-1500.

Example 370 370A

A mixture of2-[3-(2-chloroethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]-benzothiazole(625 mg), potassium iodide (332 mg), glycine tert-butyl ester,hydrochloride (503 mg) in triethylamine (630 μL) andN,N-dimethylformamide (20 mL) is heated overnight in a sealed tube at70° C., then for 16 h at 90-100° C. The mixture is cooled back to roomtemperature, poured into crushed ice and concentrated sodium hydroxidesolution. The aqueous phase is extracted with ethyl acetate. The pooledorganic phases are washed with brine, dried over magnesium sulfate andconcentrated under reduced pressure. The residue is purified bychromatography (gradient dichloromethane/methanol/ammonia from 100/0/0to 90/10/1). The crude base is converted into its salt in acetone togive(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethylamino)aceticacid tert-butyl ester, dioxalate melting at 136° C.

370B

2-[3-(2-chloroethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazolecan be obtained as described in example 272A.

370C

benzothiazol-2-yl[3-(2-chloroethoxy)phenyl]methanol can be obtained asdescribed in example 1B.

Example 371 371A

A mixture of2-[[3-(5-azidopentyloxy)phenyl](1-methyl-piperidin-4-yloxy)methyl]benzothiazole(0.13 g) and triphenylphosphine (0.11 g) in a mixture oftetrahydrofurane (3 mL) and water (2 drops) is heated at 70° C.overnight. Solvent is removed under reduced pressure. The residue isdissolved in ethyl acetate and 0.5N hydrochloric solution. The aqueousphase is washed with ethyl acetate, made alkaline with concentratedsodium hydroxide solution and extracted with ethyl acetate. The pooledextracts are washed with saturated sodium chloride solution, dried overmagnesium sulfate, concentrated under reduced pressure. The residue ispurified by column chromatography (gradientdichloromethane/methanol/ammonia from 100/0 to 90/10 1) and salifiedwith oxalic acid to give5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentylamine,oxalate melting at 141° C.

371B

A mixture of2-[[3-(5-chloropentyloxy)phenyl](1-methyl-piperidin-4-yloxy)-methyl]benzothiazole(200 mg) and sodium azide (85 mg) in dimethylsulfoxide (3 mL) is heatedovernight at 70° C., then cooled back to room temperature. Water isadded and the product is extracted with ethyl acetate. Pooled extractsare washed with water, then brine, dried over magnesium sulfate andconcentrated under reduced pressure to give2-[[3-(5-azidopentyloxy)phenyl](1-methyl-piperidin-4-yloxy)methyl]benzothiazoleused without further purification.

371C

2-[[3-(5-chloropentyloxy)phenyl](1-methyl-piperidin-4-yloxy)methyl]benzothiazolecan be prepared according to the procedures described in examples 272Aand 1B.

Further examples can be prepared according to the described generalmethods:

General Melting Example Product methods point 552-[(3-isopropoxyphenyl)(1-methylpiperidin-4- 1A, 1B 68° C.yloxy)methyl]benzothiazole, oxalate 58[benzothiazol-2-yl(1H-pyrrol-2-yl)methyl](1- 21A, 21B, 125° C.methylpiperidin-4-yl)amine 42C, 1B 60[(1H-benzimidazol-2-yl)(3-trifluoromethoxyphenyl)- 59A, 59B 82° C.methyl](1-methylpiperidin-4-yl)amine 61[(1H-benzimidazol-2-yl)(3-ethylphenyl)methyl](1- 59A, 59B 76° C.methylpiperidin-4-yl)amine 65[(1H-benzimidazol-2-yl)(3-benzyloxyphenyl)- 59A, 59B 78° C.methyl](1-methylpiperidin-4-yl)amine 66[(1H-benzimidazol-2-yl)(3-isopropylphenyl)- 59A, 59B 82° C.methyl](1-methylpiperidin-4-yl)amine 67[(1H-benzimidazol-2-yl)(3-isobutoxyphenyl)- 59A, 59B 99° C.methyl](1-methylpiperidin-4-yl)amine 68{(1H-benzimidazol-2-yl)[3-(3-methylbutoxy)- 59A, 59B 70° C.phenyl]methyl}(1-methylpiperidin-4-yl)amine 69[(1H-benzimidazol-2-yl)(3-butoxyphenyl)methyl](1- 59A, 59B 137° C.methylpiperidin-4-yl)amine, oxalate 70[(1H-benzimidazol-2-yl)(3-methoxyphenyl)- 59A, 59B 182° C.methyl](1-methylpiperidin-4-yl)amine 73[(1H-benzimidazol-2-yl)(3-cyclohexylmethoxy- 59A, 59B 88° C.phenyl)methyl](1-methylpiperidin-4-yl)amine 74[(1H-benzimidazol-2-yl)(3-fluorophenyl)methyl](1- 59A, 59B 155° C.methylpiperidin-4-yl)amine, oxalate 75[(1H-benzimidazol-2-yl)(3-methylsulfanylphenyl)- 59A, 59B 166° C.methyl](1-methylpiperidin-4-yl)amine 76[(1H-benzimidazol-2-yl)(3-hexylphenyl)methyl](1- 59A, 59B 115° C.methylpiperidin-4-yl)amine, oxalate 77[(1H-benzimidazol-2-yl)(3-isopropoxyphenyl)- 59A, 59B 75° C.methyl](1-methylpiperidin-4-yl)amine 83[(1H-benzimidazol-2-yl)(3-ethoxyphenyl)methyl](1- 59A, 59B 74° C.methylpiperidin-4-yl)amine 84 [(1H-benzimidazol-2-yl)(m-tolyl)methyl](1-59A, 59B 132° C. methylpiperidin-4-yl)amine, oxalate 85[(1H-benzimidazol-2-yl)(3-phenoxyphenyl)- 59A, 59B 144° C.methyl](1-methylpiperidin-4-yl)amine, oxalate 88[benzothiazol-2-yl(3-isopropoxyphenyl)methyl](1- 21A, 21B, 96° C.methylpiperidin-4-yl)amine, oxalate 21C, 1B 168B 901-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 59A, 59B* 198° C.ylamino)methyl]phenyl}ethanone 922-[(3-butoxyphenyl)(1-methylpiperidin-4- 1A, 1B 135° C.yloxy)methyl]benzothiazole, oxalate 93[benzothiazol-2-yl(3-cyclohexylmethoxyphenyl)- 21A, 37B, 98° C.methyl](1-methylpiperidin-4-yl)amine, oxalate 42C, 1B 168B 94[(1H-benzimidazol-2-yl)biphenyl-3-ylmethyl](1- 59A, 59B 98° C.methylpiperidin-4-yl)amine 95[(1H-benzimidazol-2-yl)(3-pentyloxyphenyl)- 59A, 59B 128° C.methyl](1-methylpiperidin-4-yl)amine, oxalate 102(benzothiazol-2-ylbiphenyl-3-ylmethyl)(1- 21A, 37B, 112° C.methylpiperidin-4-yl)amine, oxalate 21C, 1B 168B 103{(1H-benzimidazol-2-yl)[3-(4-fluorobenzyloxy)- 59A, 59B 140° C.phenyl]methyl}(1-methylpiperidin-4-yl)amine, oxalate 104[(1H-benzimidazol-2-yl)(3-benzylsulfanylphenyl)- 59A, 59B 127° C.methyl](1-methylpiperidin-4-yl)amine, oxalate 105{(1H-benzimidazol-2-yl)[3-(3- 59A, 59B 116° C.fluorobenzyloxy)phenyl]methyl}(1-methylpiperidin-4- yl)amine, oxalate106 {(1H-benzimidazol-2-yl)[3-(2-phenoxyethoxy)- 59A, 59B 140° C.phenyl]methyl}(1-methylpiperidin-4-yl)amine, oxalate 107[benzothiazol-2-yl(3-benzylsulfanylphenyl)- 91A 50° C.methyl](1-methylpiperidin-4-yl)amine, oxalate 168B 1081-{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 53 115° C.yloxy)methyl]biphenyl-4-yl}ethanone, dioxalate 1092-[(3′-fluoro-biphenyl-3-yl)(1-methylpiperidin-4- 53 120° C.yloxy)methyl]-1H-benzimidazole, dioxalate 1101-{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 53 140° C.yloxy)methyl]biphenyl-3-yl}ethanone, dioxalate 111[benzothiazol-2-yl(3-methylsulfanylphenyl)- 91A 85° C.methyl](1-methylpiperidin-4-yl)amine, oxalate 168B 112[(3-allyloxyphenyl)(1H-benzimidazol-2-yl)methyl](1- 59A, 59B 125° C.methylpiperidin-4-yl)amine, oxalate 113{(1H-benzimidazol-2-yl)[3-(2-fluorobenzyloxy)- 59A, 59B 118° C.phenyl]methyl}(1-methylpiperidin-4-yl)amine, oxalate 1142-[(1-methylpiperidin-4-yloxy)(2′-methylsulfanyl- 53 163° C.biphenyl-3-yl)methyl]-1H-benzimidazole 1152-[(4′-fluorobiphenyl-3-yl)(1-methylpiperidin-4- 53 100° C.yloxy)methyl]-1H-benzimidazole, oxalate 1162-[(1-methylpiperidin-4-yloxy)(3′-methylsulfanyl- 53 80° C.biphenyl-3-yl)methyl]-1H-benzimidazole, dioxalate 1192-[(1-methylpiperidin-4-yloxy)(4′-trifluoromethyl- 53 95° C.biphenyl-3-yl)methyl]-1H-benzimidazole 120{(1H-benzimidazol-2-yl)[3-(tetrahydropyran-2- 59A, 59B 97° C.yloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine 1212-[(2′-Chlorobiphenyl-3-yl)(1-methylpiperidin-4- 53 130° C.yloxy)methyl]-1H-benzimidazole, oxalate 1222-[(3′,4′-dichlorobiphenyl-3-yl)(1-methylpiperidin-4- 53 150° C.yloxy)methyl]-1H-benzimidazole, oxalate 123{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 53 107° C.yloxy)methyl]biphenyl-2-yl}methanol 124{(1H-benzimidazol-2-yl)[3-(4-methoxybenzyloxy)- 59A, 59B 84° C.phenyl]methyl}(1-methylpiperidin-4-yl)amine 125{(1H-benzimidazol-2-yl)[3-(3-methoxybenzyloxy)- 59A, 59B 135° C.phenyl]methyl}(1-methylpiperidin-4-yl)amine, oxalate 127{3′-[benzothiazol-2-yl(1-methylpiperidin-4- 53 206-207° C.yloxy)methyl]biphenyl-2-yl}methanol, oxalate 129{(1H-benzimidazol-2-yl)[3-(2-methylbenzyloxy)- 59A, 59B 121° C.phenyl]methyl}(1-methylpiperidin-4-yl)amine, oxalate 130{(1H-benzimidazol-2-yl)[3-(4-methylbenzyloxy)- 59A, 59B 87° C.phenyl]methyl}(1-methylpiperidin-4-yl)amine 132[(3-azidophenyl)(1H-benzimidazol-2-yl)methyl](1- 131, 231A, 202° C.methylpiperidin-4-yl)amine 231B 138{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 53 135° C.yloxy)methyl]biphenyl-4-yl}carbamic acid tert-butyl ester 1422-[(2′-fluorobiphenyl-3-yl)(1-methylpiperidin-4- 53 90° C.yloxy)methyl]-1H-benzimidazole 144 [(1H-benzimidazol-2-yl)(3-furan-2-59A, 59B 108° C. ylphenyl)methyl](1-methylpiperidin-4-yl)amine 145[(1H-benzimidazol-2-yl)(3-but-3-enyloxyphenyl)- 59A, 59B 71° C.methyl](1-methylpiperidin-4-yl)amine 146{(1H-benzimidazol-2-yl)[3-(4-methylpentyloxy)- 59A, 59B 73° C.phenyl]methyl}(1-methylpiperidin-4-yl)amine 149{(1H-benzimidazol-2-yl)[3-(2,5-difluoro- 59A, 59B 159° C.benzyloxy)phenyl]methyl}(1-methylpiperidin-4- yl)amine, oxalate 1512-[(2-chlorophenyl)(1-methylpiperidin-4- 72A, 72B 212° C.yloxy)methyl]-1H-benzimidazole 1522-[(3-ethylphenyl)(1-methylpiperidin-4- 1A, 168B 123° C.yloxy)methyl]benzothiazole, oxalate 1552-[(3-fluorophenyl)(1-methylpiperidin-4- 72A, 72B, 93° C.yloxy)methyl]-1H-benzimidazole 72C 1612-[[3-(2,3-difluorobenzyloxy)phenyl](1- 1A, 168B 98° C.methylpiperidin-4-yloxy)methyl]benzothiazole, oxalate 162{(1H-benzimidazol-2-yl)[3-(2,3-difluoro- 59A, 59B 151° C.benzyloxy)phenyl]methyl}(1-methylpiperidin-4- yl)amine 1632-[[3-(2-fluoroethoxy)phenyl](1-methylpiperidin-4- 1A, 168B 147° C.yloxy)methyl]benzothiazole, oxalate 1642-[(1-methylpiperidin-4-yloxy)(m-tolyl)methyl]-1H- 72A, 72B, 119° C.benzimidazole 72C 166 5-fluoro-2-[(1-methylpiperidin-4- 165 134° C.yloxy)phenylmethyl]-1H-benzimidazole 1672-[(2-fluorophenyl)(1-methylpiperidin-4- 72A, 72B, 181° C.yloxy)methyl]-1H-benzimidazole 72C 1692-{(1-methylpiperidin-4-yloxy)[3-(4,4,4-trifluoro- 1A, 168B 115° C.butoxy)phenyl]methyl}benzothiazole, oxalate 1705-bromo-2-[(1-methylpiperidin-4- 165 143° C.yloxy)phenylmethyl]-1H-benzimidazole 1712-[[3-(3-fluorobenzyloxy)phenyl](1-methylpiperidin- 1A, 168B 65° C.4-yloxy)methyl]benzothiazole, oxalate 174((1H-benzimidazol-2-yl)-{3-[3-(2-methyl- 59A, 59B* 120° C.[1,3]dioxolan-2-yl)-propoxy]phenyl}methyl)(1-methylpiperidin-4-yl)amine, oxalate 175{(1H-benzimidazol-2-yl)[3-(4,4,4-trifluoro- 59A, 59B 94° C.butoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine 1762-[[3-(3-fluoropropoxy)phenyl](1-methylpiperidin-4- 1A, 1B 72° C.yloxy)methyl]benzothiazole, oxalate 1772-[(1-methylpiperidin-4-yloxy)-p-tolyl-methyl]-1H- 72A, 72B, 102° C.benzimidazole 72C 179 2-[(4-fluorophenyl)(1-methylpiperidin-4- 72A, 72B,131° C. yloxy)methyl]-1H-benzimidazole 72C 180{(1H-benzimidazol-2-yl)[3-(2-fluoro- 59A, 59B 155° C.ethoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine, oxalate 181((1H-benzimidazol-2-yl)-{3-[2-(6,6-dimethyl- 59A, 59B 123° C.bicyclo[3.1.1]hept-2-en-2- yl)ethoxy]phenyl}methyl)(1-methylpiperidin-4-yl)amine, oxalate 182 2-[(1-methylpiperidin-4-yloxy)(4′-trifluoro- 5390° C. methoxybiphenyl-3-yl)methyl]-1H-benzimidazole 1832-[(4′-methoxybiphenyl-3-yl)(1-methylpiperidin-4- 53 92° C.yloxy)methyl]-1H-benzimidazole 1842-[(3-benzo[1,3]dioxol-5-ylphenyl)(1-methyl- 53 95° C.piperidin-4-yloxy)methyl]-1H-benzimidazole 1852-[[3-(3-methoxybenzyloxy)phenyl](1-methyl- 1A, 168B 77° C.piperidin-4-yloxy)methyl]benzothiazole, oxalate 1865-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 1A, 168B, * 72° C.yloxy)methyl]phenoxy}pentan-2-one, oxalate 1872-{(1-methylpiperidin-4-yloxy)[3-(3-trifluoromethyl- 1A, 168B 80° C.benzyloxy)phenyl]methyl}benzothiazole, oxalate 1903-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 189 117-120° C.yloxy)methyl]phenyl}prop-2-yn-1-ol 1914-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 189 104-108° C.yloxy)methyl]phenyl}but-3-yn-1-ol 1925-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 189 85° C.yloxy)methyl]phenyl}pent-4-yn-1-ol 1932-[(1-methylpiperidin-4-yloxy)-o-tolyl-methyl]-1H- 72A, 72B, 190° C.benzimidazole 72C 197 3-[benzothiazol-2-yl(1-methylpiperidin-4- 72A, 1B75° C. yloxy)methyl]benzonitrile, oxalate 2042-[(4-bromophenyl)(1-methylpiperidin-4- 72A, 72B, 122° C.yloxy)methyl]-1H-benzimidazole 72C 2132-[(2-chloro-4-methylphenyl)(1-methylpiperidin-4- 72A, 272B 96° C.yloxy)methyl]-1H-benzimidazole, oxalate 2145-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 53 170° C.yloxy)methyl]phenyl}pyrimidin-2-ol 2162-[(1-methylpiperidin-4-yloxy)(3-pyrimidin-5-yl- 53 85° C.phenyl)methyl]benzothiazole 218 2-[(1-methylpiperidin-4-yloxy)(3-vinyl-217 165° C. phenyl)methyl]benzothiazole 2203-[benzothiazol-2-yl(1-methylpiperidin-4- 219 60° C.yloxy)methyl]-N-propylbenzamide 2212-[(2,4-difluorophenyl)(1-methylpiperidin-4- 72A, 272B 106° C.yloxy)methyl]-1H-benzimidazole, oxalate 222[(1H-benzimidazol-2-yl)(4′-methoxy-biphenyl-3- 21A, 37B, 110° C.yl)methyl](1-methylpiperidin-4-yl)amine 211B, 42C, 272B 2233-[benzothiazol-2-yl(1-methylpiperidin-4- 219 125° C.yloxy)methyl]-N-methyl-N-phenylbenzamide, oxalate 2252-[(3-chlorophenyl)(1-methylpiperidin-4- 72A, 272B 158° C.yloxy)methyl]-1H-benzimidazole, oxalate 2262-[(4-chlorophenyl)(1-methylpiperidin-4- 72A, 272B 175° C.yloxy)methyl]-1H-benzimidazole, oxalate 2353-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 150 80° C.yloxy)methyl]phenylsulfanyl}-3-methyl-butan-1-ol 2423-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 148 80° C.yloxy)methyl]phenylsulfanyl}-3-methyl-butan-1-ol, oxalate 2432-[(1-methylpiperidin-4-yloxy)(3-morpholin-4-yl- 234 111° C.phenyl)methyl]benzothiazole, oxalate 2442-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 234 45° C.yloxy)methyl]phenoxy}ethanol, oxalate 2463-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 150 97-99° C.yloxy)methyl]phenylsulfanyl}propan-1-ol 2471-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 150 120-122° C.yloxy)methyl]phenylsulfanyl}propan-2-ol 2502-{(1-methylpiperidin-4-yloxy)[3-(2-methylsulfanyl- 272A, 1B 89° C.ethoxy)phenyl]methyl}benzothiazole, oxalate 2512-[(1-methylpiperidin-4-yloxy)(2-trifluoromethoxy- 72A, 272B 193° C.phenyl)methyl]-1H-benzimidazole 2612-[(3-bromo-4-methylphenyl)(1-methylpiperidin-4- 72A, 272B 92° C.yloxy)methyl]-1H-benzimidazole 2622-[(2-bromophenyl)(1-methylpiperidin-4- 72A, 272B 213° C.yloxy)methyl]-1H-benzimidazole 2652-{(1-methylpiperidin-4-yloxy)[3-(pyridin-4- 258 101° C.ylmethoxy)phenyl]methyl}benzothiazole, oxalate 2664-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 258 63° C.yloxy)methyl]phenoxy}butan-1-ol, oxalate 2672-[[3-(furan-2-ylmethoxy)phenyl](1- 258 85° C.methylpiperidin-4-yloxy)methyl]benzothiazole, oxalate 2692-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 249, 149A 80° C.yloxy)methyl]phenylsulfanyl}ethylamine, dioxalate 2712-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 371A, 371B, 76° C.yloxy)methyl]phenoxy}ethylamine 272A, 1B 273[(1H-benzimidazol-2-yl)-p-tolyl-methyl](1- 59A, 59C 183° C.methylpiperidin-4-yl)amine 274 2-[(3-ethylsulfanyl-4-methylphenyl)(1-148, 272A, 142° C. methylpiperidin-4-yloxy)methyl]-1H- 272Bbenzimidazole, oxalate 2772-[[3-(2-methoxyethoxy)phenyl](1-methylpiperidin- 1A, 1B 80° C.4-yloxy)methyl]benzothiazole, oxalate 279(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 258 125° C.yloxy)methyl]phenoxy}ethyl)methyl-amine, dioxalate 2802-[(1-methylpiperidin-4-yloxy)(3-trifluoromethoxy- 272A, 272B 172° C.phenyl)methyl]-1H-benzimidazole, oxalate 2812-[(2-Chlorophenyl)(1-methylpiperidin-4- 272A, 1B 163° C.yloxy)methyl]benzothiazole, oxalate 2832-{(1-methylpiperidin-4-yloxy)[3-(pyridin-2- 272A, 1B 158° C.ylmethoxy)phenyl]methyl}benzothiazole, oxalate 2842-{(1-methylpiperidin-4-yloxy)[3-(pyridin-3- 272A, 1B 102° C.ylmethoxy)phenyl]methyl}benzothiazole, oxalate 2852-[(3-Cyclohexylmethoxyphenyl)(1- 1A, 1B 101° C.methylpiperidin-4-yloxy)methyl]benzothiazole, oxalate 2895-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 293, 194 110° C.yloxy)methyl]phenyl}pentylamine, dihydrochloride 2902-{3-[benzothiazol-2-yl(1-ethyl-piperidin-4- 371A, 371B, 112° C.yloxy)methyl]phenoxy}ethylamine, dioxalate 272A, 1B 2912-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 371A, 371B, 90° C.yloxy)methyl]phenoxy}ethylamine 272A, 272B 2926-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 148 80° C.yloxy)methyl]phenylsulfanyl}hexan-1-ol, oxalate 3002-[(2,3-dihydrobenzo[1,4]dioxin-6-yl)(1- 272A, 272B 203° C.methylpiperidin-4-yloxy)methyl]-1H-benzimidazole 302N-(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 278A, 249, 125° C.yloxy)methyl]phenylsulfanyl}ethyl)guanidine, 149A hydrochloride 304N-tert-butoxycarbonyl-N′-(2-{3-[(benzothiazol-2- 307A, 194A 110° C.yl)(1-methylpiperidin-4- yloxy)methyl]phenylsulfanyl}ethyl)guanidine 3062-[{3-[2-(1-methyl-1H-imidazol-4-yl)ethyl]- 293, 194 80° C.phenyl}(1-methylpiperidin-4-yloxy)methyl]- benzothiazole, oxalate 3102-{(1-methylpiperidin-4-yloxy)[3-(pyridin-2- 272A, 272B 77° C.ylmethoxy)phenyl]methyl}-1H-benzimidazole 3113-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 371A, 371B, 120° C.yloxy)methyl]phenoxy}propylamine, oxalate 272A, 1B 3143-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 305A, 305B 99° C.yloxy)methyl]phenylsulfanyl}propylamine, oxalate 3196-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 194, 189 135° C.yloxy)methyl]phenyl}hex-5-ynylamine, oxalate 3222-{(1-methylpiperidin-4-yloxy)[3-(4-morpholin-4-yl- 370A, 272A, 61° C.butoxy)phenyl]methyl}benzothiazole,oxalate 1B 323(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 258 76° C.yloxy)methyl]phenyl}pyrrolidin-2-yl)methanol, oxalate 324(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 258 99° C.yloxy)methyl]phenyl}pyrrolidin-2-yl)methanol, oxalate 3256-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 293, 194 115° C.yloxy)methyl]phenyl}hexylamine, oxalate 3264-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 305A, 305B 146° C.yloxy)methyl]phenylsulfanyl}butylamine, oxalate 3273-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 371A, 371B, 97° C.yloxy)methyl]phenoxy}propylamine 272A, 272B 3294-(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 370A, 272A; 90° C.yloxy)methyl]phenoxy}ethyl)piperazine-1- 1B carboxylic acid tert-butylester, oxalate 331 4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-371A, 371B, 115° C. yloxy)methyl]phenoxy}butylamine, oxalate 272A, 272B332 2-{(1-methylpiperidin-4-yloxy)[3-(4-morpholin-4-yl- 370A, 272A, 85°C. butoxy)phenyl]methyl}-1H-benzimidazole, oxalate 272B 3332-{(1-methylpiperidin-4-yloxy)[3-(4-piperidin-1-yl- 370A, 272A, 130° C.butoxy)phenyl]methyl}-1H-benzimidazole, oxalate 272B 3342-[(2-fluoro-3-iodophenyl)(1-methylpiperidin-4- 272A, 272B 125° C.yloxy)methyl]-1H-benzimidazole 339N-tert-butoxycarbonyl-N′-(5-{3-[(benzothiazol-2- 307A, 194A 125° C.yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent- 5-ynyl)guanidine 340N-(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 180° C.yloxy)methyl]phenyl}pent-4-ynyl)guanidine, hydrochloride 341N-tert-butoxycarbonyl-N′-(6-{3-[(benzothiazol-2- 307A, 194A 130° C.yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5- ynyl)guanidine 342N-(6-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 185° C.yloxy)methyl]phenyl}hex-5-ynyl)guanidine, hydrochloride 3434-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin- 370A, 272A, 64° C.4-yloxy)methyl]phenoxy}butyl)piperazine-1- 272B carboxylic acidtert-butyl ester 3482-{(1-methylpiperidin-4-yloxy)[3-(3-[1,2,4]triazol-1- 315A, 272A, 60° C.yl-propoxy)phenyl]methyl}benzothiazole,oxalate 1B 3492-{(1-methylpiperidin-4-yloxy)[3-(3-[1,2,3]triazol-2- 315A, 272A, 74° C.yl-propoxy)phenyl]methyl}benzothiazole, oxalate 1B (contains 23% of1,2,3-triazol-1-yl compound) 3502-{(1-methylpiperidin-4-yloxy)[3-(3-morpholin-4-yl- 370A, 272A, 105° C.propoxy)phenyl]methyl}benzothiazole, oxalate 1B 3522-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 423A, 150A, 204° C.yloxy)methyl]-2-fluorophenylsulfanyl}ethylamine 272A, 272B 3542-[[3-(2-Chloroethoxy)phenyl](1-methylpiperidin-4- 272A, 1B 70° C.yloxy)methyl]benzothiazole, oxalate 3562-{(1-methylpiperidin-4-yloxy)[3-(2-piperidin-1-yl- 370A, 272A, 160° C.ethoxy)phenyl]methyl}-1H-benzimidazole, oxalate 272B 3604-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin- 370A, 272A, 140° C.4-yloxy)methyl]phenoxy}propyl)piperazine-1- 272B carboxylic acidtert-butyl ester, oxalate 3624-(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 370A, 272A, 131° C.yloxy)methyl]phenoxy}pentyl)piperazine-1- 1B carboxylic acid tert-butylester 363 N-(6-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 278A, 249, 90°C. yloxy)methyl]phenyl}hexyl)guanidine, 149A hydrochloride 364N-tert-butoxycarbonyl-N′-(6-{3-[(1H-benzimidazol- 307A, 194A 90° C.2-yl)(1-methylpiperidin-4- yloxy)methyl]phenyl}hexyl)guanidine 365N-(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 278A, 249, 90° C.yloxy)methyl]phenyl}pentyl)guanidine, 149A hydrochloride 3664-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 293, 194 100° C.yloxy)methyl]phenyl}butylamine, dioxalate 367[[3-(4-aminobutoxy)phenyl](1H-benzimidazol-2- 21A, 37B, 68° C.yl)methyl](1-methylpiperidin-4-yl)amine 371B, 42C, 272B 3683-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 278A, 249, 126° C.yloxy)methyl]phenylsulfanyl}propylamine 149A 3694-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin- 370A, 272A; 92° C.4-yloxy)methyl]phenoxy}ethyl)piperazine-1- 1B carboxylic acid tert-butylester, dioxalate 373 N-(3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-278A, 249, 125° C. yloxy)methyl]phenyl}prop-2-ynyl)guanidine, 149Atrihydrochloride 374 N-(4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-278A, 249, 120° C. yloxy)methyl]phenyl}butyl)guanidine, 149Atrihydrochloride 375 (5-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 370A,272A, 99° C. yloxy)methyl]phenoxy}pentylamino)acetic acid 1B tert-butylester, oxalate 377 2-{(1-methylpiperidin-4-yloxy)[3-(piperidin-4- 423A,258 90° C. ylmethoxy)phenyl]methyl}benzothiazole, dioxalate 3782-{(1-methylpiperidin-4-yloxy)[3-(piperidin-3- 423A, 258 55° C.ylmethoxy)phenyl]methyl}benzothiazole, dioxalate 3792-[[3-(1-methylpiperidin-3-ylmethoxy)phenyl](1- 165C, 423A, 76° C.methylpiperidin-4-yloxy)methyl]benzothiazole, 258 dioxalate 3802-[(1-methylpiperidin-4-yloxy)(3-piperidin-3- 376A, 189 97° C.ylethynylphenyl)methyl]-1H-benzimidazole 3815-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 305A, 305B 140° C.yloxy)methyl]phenylsulfanyl}pentylamine, oxalate 3822-{(1-methylpiperidin-4-yloxy)[3-(pyrrolidin-3- 258 50° C.yloxy)phenyl]methyl}benzothiazole, dioxalate 387{[3-(4-aminobutoxy)phenyl]benzothiazol-2-yl- 21A, 37B, 67° C.methyl}(1-methylpiperidin-4-yl)amine 371B, 42C, 1B 3882-[(3-azetidin-3-ylethynylphenyl)(1- 249, 293, 189 131° C.methylpiperidin-4-yloxy)methyl]-1H-benzimidazole 3895-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 384A, 53 125° C.yloxy)methyl]phenyl}pent-4-en-1-ol, oxalate 3914-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin- 370A, 72A, 101° C.4-yloxy)methyl]phenoxy}pentyl)piperazine-1- 272B carboxylic acidtert-butyl ester, dioxalate 392 2-[[3-(2-azetidin-3-ylethyl)phenyl](1-249, 189 146° C. methylpiperidin-4-yloxy)methyl]-1H-benzimidazole 3952-{(1-methylpiperidin-4-yloxy)[3-(2-piperidin-2-yl- 249, 149A 164° C.ethylsulfanyl)phenyl]methyl}-1H-benzimidazole 399N-tert-butoxycarbonyl-N′-(4-{3-[(benzothiazol-2- 307A, 194A 120° C.yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3- ynyl)guanidine 4005-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 371A, 371B, 111° C.yloxy)methyl]phenoxy}pentylamine, dioxalate 72A, 272B 4022-[[3-(azetidin-3-yloxy)phenyl](1-methylpiperidin- 423A, 258 81° C.4-yloxy)methyl]benzothiazole, dioxalate 404(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 403 106° C.yloxy)methyl]phenyl}pyrrolidin-3-yl)methanol, oxalate 4051-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 423A, 403 137° C.yloxy)methyl]phenyl}piperidin-4-ylamine, dioxalate 4061-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 403 103° C.yloxy)methyl]phenyl}pyrrolidin-3-ol, oxalate 4071-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 403 106° C.yloxy)methyl]phenyl}pyrrolidin-3-ol, oxalate 408N-(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 403 111° C.yloxy)methyl]phenyl}pyrrolidin-3-yl)acetamide, oxalate 4102-{(1-methylpiperidin-4-yloxy)[3-(5-pyrazol-1-yl- 416A, 189 115° C.pent-1-ynyl)phenyl]methyl}-1H-benzimidazole, oxalate 413 acetic acid1-{3-[benzothiazol-2-yl(1-methyl- 403 74° C.piperidin-4-yloxy)methyl]phenyl}piperidin-4-yl ester, oxalate 4142-[(3-bromo-phenyl)(1-methylpyrrolidin-3- 165C, 272A, 61° C.ylmethoxy)methyl]-1H-benzimidazole 72B, 72C 4152-{(1-methylpiperidin-4-yloxy)[3-(piperidin-4- 423A, 258 76° C.yloxy)phenyl]methyl}benzothiazole, dioxalate 419N1-(5-{3-[(1H-benzimidazol-2-yl)(1-methyl- 423A, 370A, 162° C.piperidin-4-yloxy)methyl]phenoxy}pentyl)butane- 72A, 272B 1,4-diamine,dioxalate 420 {[3-(6-aminohex-1-ynyl)phenyl]benzothiazol-2-yl- 386A, 27580° C. methyl}(1-methylpiperidin-4-yl)amine, oxalate 4224-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 258 73° C.yloxy)methyl]phenoxy}but-2-en-1-ol, oxalate 4242-[(2,5-difluorophenyl)(1-methylpiperidin-4- 272A, 272B 140° C.yloxy)methyl]-1H-benzimidazole 4252-[(2-fluoro-5-iodo-phenyl)(1-methylpiperidin-4- 272A, 272B 175° C.yloxy)methyl]-1H-benzimidazole, dioxalate 4274-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methyl- 150 85° C.piperidin-4-yloxy)methyl]phenylsulfanyl}butan-1-ol 4282-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methyl- 249, 149A 85° C.piperidin-4-yloxy)methyl]phenylsulfanyl}- ethylamine, dioxalate 4291-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 423A, 423B 137° C.yloxy)methyl]phenyl}pyrrolidin-3-ylamine, dioxalate 4302-[[3-(3-fluoropyrrolidin-1-yl)phenyl](1- 423B 70° C.methylpiperidin-4-yloxy)methyl]benzothiazole, oxalate 4314-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 386A, 424A, 117° C.yloxy)methyl]phenoxy}but-2-enylamine, dioxalate 258 4332-[(2-fluoro-5-trifluoromethoxyphenyl)(1- 272A, 272B 95° C.methylpiperidin-4-yloxy)methyl]-1H-benzimidazole *in the case ofketone-containing substituents, it is judicious to protect the carbonylfunction (as an acetal for example) prior to the Grignard preparation

Example 4342-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazoleenantiomer A

A solution of racemic2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole(1 mg/mL) in a mixture of heptane/isopropanol (90/10) containingdiethylamine (0.1%) is injected (10 μL) onto an analytical ChiralpakAD-H, 250×4.6 mm column. Elution is performed with a mixture ofheptane/isopropanol (90/10) containing diethylamine (0.1%) at a flow of1 mL/min. Products are detected at 220 nm.

The first enantiomer has a retention time of 6.9 min.

Collection affords2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazoleenantiomer A with a chromatographic enantiomeric purity of 99.8%.

Example 4352-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazoleenantiomer B

The second enantiomer has a retention time of 8.3 min.

Collection affords 2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole enantiomer B with achromatographic enantiomeric purity of 96.8%.

Following compounds are prepared using general methods described inexample 1:

Example Product 782-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H- benzimidazole¹H NMR: 9.62 (sl, 1H), 7.85-7.70 (m, 1H), 7.65 (s, 1H), 7.50-7.35 (m,3H), 7.30-7.15 (m, 3H), 5.84 (s, 1H), 3.65-3.50 (m, 1H), 2.85-2.65 (m,2H), 2.28 (s, 3H), 2.25-1.60 (m, 6H)

80 2-[(3-butylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole 80A

To a mixture of trifluoromethanesulfonic acid3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl ester (110mg) and ferric acetylacetonate (4 mg) in a mixture of tetrahydrofurane(4.5 mL) and N-methylpyrrolidone (0.25 mL) cooled at 0° C. is added a 2Msolution of butylmagnesium chloride in tetrahydrofurane (150 μL). Themixture is stirred at room temperature for 25 min, then warmed at 30° C.for 15 min. A second addition of butylmagnesium chloride intetrahydrofurane (150 μL) is performed. The mixture is then diluted withdiethyl ether and quenched with 0.5N hydrochloric solution. The aqueousphase is extracted with diethyl ether, then ethyl acetate. Organicphases are pooled, dried over magnesium sulfate and concentrated underreduced pressure. The residue is purified by chromatography (gradientheptane/ethyl acetate from 99/1 to 90/10). The product is then refluxedin methanol and concentrated to give2-[(3-butylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole.

TLC (eluent: CH₂Cl₂/MeOH 90/10): Rf=0.30

80B

To a solution of3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenol (318 mg) inpyridine (74 μL) and dichloromethane (3 mL) cooled at −5° C. is addedtrifluoromethanesulfonic anhydride (152 μL). The mixture is stirred for1 h, then allowed to warm to room temperature. The organic phase iswashed with water, dried over magnesium sulfate and concentrated underreduced pressure. The residue is purified by chromatography (gradientheptane/ethyl acetate from 95/5 to 50/50) to givetrifluoromethanesulfonic acid3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl ester usedwithout further purification.

Following compounds are prepared using general methods described inexample 21A, 21C and 1B:

Example Product 82[benzothiazol-2-yl(3-bromophenyl)methyl](1-methylpiperidin- 4-yl)amine¹H NMR (DMSO d⁶): 9.21 (sl, 1H), 8.02 (d, 1H), 7.85 (d, 1H), 7.52-7.20(m, 6H), 5.39 (s, 1H), 3.45-3.30 (m, 1H), 3.05-2.80 (m, 2H), 2.75-2.55(m, 2H), 2.65 (s, 3H), 2.25-1.85 (m, 2H), 1.80-1.45 (m, 2H)

Example 1172-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazoleenantiomer A

A solution of racemic2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-benzothiazole (10mg/mL) in a mixture of heptane/isopropanol (80/20) containingdiethylamine (0.1%) is injected (20×100 μL) onto an analytical ChiralpakAD-H, 250×4.6 mm column. Elution is performed with a mixture ofheptane/isopropanol (80/20) containing diethylamine (0.1%) at a flow of1 mL/min. Products are detected at 220 nm.

The first enantiomer has a retention time of 6.0 min.

Collection affords2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazoleenantiomer A with a chromatographic enantiomeric purity of 97.3%.

Example 1182-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazoleenantiomer B

The second enantiomer has a retention time of 7.0 min.

Collection affords2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazoleenantiomer B with a chromatographic enantiomeric purity of 99.7%.

Example 1263-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-ylamino)methyl]phenol

A solution of{(1H-benzimidazol-2-yl)[3-(tetrahydropyran-2-yloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine(example 120, 500 mg) in ethanol (5 mL) is treated with aqueous 37%hydrochloric acid at room temperature for one night. The mixture is thenneutralized with an aqueous saturated sodium hydrogen carbonate solutionand extracted with ethyl acetate. The pooled organic extracts are driedover magnesium sulfate and concentrated under reduced pressure. Theresidue is purified by column chromatography (gradientdichloromethane/methanol/ammonia from 90/10/0.5 to 80/20/0.5) to give3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-ylamino)methyl]phenol as awhite solid melting at 230° C.

Example 131[(1H-benzimidazol-2-yl)(3-nitrophenyl)methyl](1-methylpiperidin-4-yl)amine131A

To a solution of[(1H-benzimidazol-2-yl)(3-nitrophenyl)methylene](1-methylpiperidin-4-yl)amine(1.1 g) in methanol (50 mL) at 0° C. is added sodium cyanoborohydride,then dropwise acetic acid (0.19 mL). The reaction mixture is allowed toreach room temperature and stirred at that temperature overnight.

Cold water (70 mL) is added as well as concentrated hydrochloric acid toreach pH 1. Then a concentrated sodium hydroxide solution is added toreach pH 10. The aqueous phase is extracted with dichloromethane. Thepooled organic extracts are dried over magnesium sulfate andconcentrated under reduced pressure. The residue is purified bychromatography (gradient dichloromethane/methanol from 99/1 to 95/5) toafford[(1H-benzimidazol-2-yl)(3-nitrophenyl)methyl](1-methylpiperidin-4-yl)aminemelting at 254° C.

131B

[(1H-benzimidazol-2-yl)(3-nitrophenyl)methylene](1-methylpiperidin-4-yl)aminecan be prepared according to the method described in example 37B.

Further examples can be prepared according to the described generalmethods:

Example Product General methods TLC 222-[(3-allyloxyphenyl)(1-methylpiperidin-4- 1A, 1B 0.41(C)yloxy)methyl]benzothiazole, hydrochloride 322-[(2,3-dihydrobenzofuran-5-yl)(1-methyl- 1A, 1B 0.32(C)piperidin-4-yloxy)methyl]benzothiazole, oxalate 71trifluoromethanesulfonic acid 3-[benzothiazol- 1A, 1B 0.50(D)2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl ester 101[benzothiazol-2-yl(3-benzyloxyphenyl)- 91A, 1B 0.17(C)methyl](1-methylpiperidin-4-yl)amine, oxalate 134{(1H-benzimidazol-2-yl)[3-(2-ethoxyethoxy)- 59A, 59B 0.26(A)phenyl]methyl}(1-methylpiperidin-4-yl)amine 135[(1H-benzimidazol-2-yl)(3-pent-4- 59A, 59B 0.16(A)enyloxyphenyl)methyl](1-methylpiperidin-4- yl)amine 1782-{(1-methylpiperidin-4-yloxy)[3-(3,3,3- 1A, 168B 0.67(D)trifluoro-propoxy)phenyl]methyl}- benzothiazole, oxalate 1962-{(1-methylpiperidin-4-yloxy)[3-(3-nitro- 1A, 1B 0.17(B)benzyloxy)phenyl]methyl}benzothiazole, oxalate 2701-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 1A, 168B* 0.32(A)yloxy)methyl]benzyloxy}propan-2-one, oxalate 2972-[benzo[1,3]dioxol-5-yl(1-methylpiperidin-4- 272A, 272B 0.22(D)yloxy)methyl]-1H-benzimidazole 3014-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 371A, 371B, 0.08(B)yloxy)methyl]phenoxy}butylamine, oxalate 272A, 1B 3284-(2-{3-[benzothiazol-2-yl(1-methylpiperidin- 370A, 272A, 0.69(D)4-yloxy)methyl]phenoxy}ethyl)piperazine-1- 1B carboxylic acid tert-butylester 330 2-{(1-methylpiperidin-4-yloxy)[3-(2-piperazin- 423A, 370A,0.26(D) 1-yl-ethoxy)phenyl]methyl}benzothiazole, 272A, 1B oxalate 361(2-{3-[(1H-benzimidazol-2-yl)(1-methyl- 370A, 272A, 0.51(D)piperidin-4-yloxy)methyl]phenoxy}- 1B ethylamino)acetic acid tert-butylester, oxalate Eluent A: CH₂Cl₂/MeOH/NH₄OH 90/10/0.5 Eluent B:CH₂Cl₂/MeOH/NH₄OH 95/5/0.5 Eluent C: CH₂Cl₂/MeOH 90/10 Eluent D:CH₂Cl₂/MeOH/NH₄OH 90/10/1 *in the case of ketone-containingsubstituents, it is judicious to protect the carbonyl function (as anacetal for example) prior to the Grignard preparation

Example 1472-[(1-methylpiperidin-4-yloxy)(3-pyrazol-1-ylphenyl)methyl]benzothiazole,oxalate

To a solution of2-[(3-Bromophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole (208mg) in N,N-dimethylformamide (1 mL) are added pyrazole (68 mg), cesiumcarbonate (401 mg) and copper(I) iodide (19 mg). The tube is evacuated,filled with argon and sealed. After stirring at 120° C. for 48 h, themixture is diluted with water and ammonia solution then extracted withethyl acetate. The pooled organic extracts are dried over magnesiumsulfate and concentrated under reduced pressure. The residue is purifiedby chromatography (gradient dichloromethane/methanol/ammonia from100/0/0 to 95/5/0.5). The residue is added to a solution of oxalic acid(1 molar equivalent) and the residual precipitate is filtered and driedto afford2-[(1-methylpiperidin-4-yloxy)(3-pyrazol-1-ylphenyl)methyl]benzothiazoleoxalate melting at 89° C.

Example 1482-[(3-benzylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole

A screw-cap tube is charged with2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole (208mg), palladium bis(dibenzylideneacetone) (14 mg), Xantphos (14 mg),benzyl mercaptan (59 μL), diisopropylethylamine (174 μL) and 1,4-dioxane(2 mL). The tube is evacuated, filled with argon and sealed. Afterstirring at 120° C. for 15 h, the mixture is diluted with ethyl acetateand water and the aqueous phase is extracted with ethyl acetate. Thepooled organic extracts are dried over magnesium sulfate andconcentrated under reduced pressure. The residue is purified bychromatography (gradient dichloromethane/methanol/ammonia from 100/0/0to 95/5/0.5). The residual yellowish oil is re-crystallized from hotacetonitrile to give2-[(3-benzylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazolemelting at 195° C.

Further examples can be prepared according to the above describedgeneral method:

Example Product 158 2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanol ¹H NMR: 7.98 (d, 1H), 7.88 (d, 1H),7.57 (s, 1H), 7.47-7.27 (m, 5H), 5.88 (s, 1H), 3.75 (t, 2H), 3.65 (m,1H), 3.12 (t, 2H), 2.70-2.81 (m, 2H), 2.30 (s, 3H), 1.7-2.4 (m, 7H) 1592-[(3-ethylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole¹H NMR: 7.98 (d, 1H), 7.88 (d, 1H), 7.50-7.30 (m, 3H), 7.30-7.10 (m,3H), 5.83 (s, 1H), 3.93 (m, 1H), 3.25-3.00 (m, 4H), 2.95 (q, 2H), 2.67(s, 3H), 2.50-2.30 (m, 2H), 2.20-2.00 (m, 2H), 1.30 (t, 3H) 160{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}aceticacid methyl ester ¹H NMR: 7.98 (d, 1H), 7.87 (d, 1H), 7.62 (s, 1H),7.50-7.29 (m, 5H), 5.85 (s, 1H), 4.02 (s, 1H), 3.74-3.65 (m, 5H),3.4-3.2 (m, 4H), 2.79 (s, 3H), 2.6-2.4 (m, 2H), 2.25-2.05 (m, 2H) 2012-[(1-methylpiperidin-4-yloxy)(3-methylsulfanyl-phenyl)methyl]benzothiazole¹H NMR: 7.97 (d, 1H), 7.87 (d, 1H), 7.50-7.10 (m, 6H), 5.89 (s, 1H),3.70-3.58 (m, 1H), 2.62-2.78 (m, 2H), 2.48 (s, 3H) 2.23 (s, 3H),2.23-2.10 (m, 2H), 2.00-1.7 (m, 4H) 2332-{(1-methylpiperidin-4-yloxy)[3-(2-pyrazin-2-yl-ethylsulfanyl)phenyl]methyl}benzothiazole ¹H NMR: 8.47 (m, 1H), 8.40 (m,1H), 7.96 (d, 1H), 7.85 (d, 1H), 7.53 (s, 1H), 7.45-7.27 (m, 6H), 5.88(s, 1H), 3.8-3.60 (m, 1H), 3.34 (t, 2H), 3.09 (t, 2H), 2.82-2.75 (m,2H), 2.34 (s, 3H), 2.50-2.20 (m, 2H), 2.1-1.70 (m, 4H) 239(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}-cyclopropyl)acetic acid methyl ester¹H NMR: 7.97 (d, 1H), 7.87 (d, 1H), 7.53 (s, 1H), 7.48-7.24 (m, 5H),5.87 (s, 1H), 3.7-3.5 (m, 4H), 3.08 (s, 2H), 2.80-2.65 (m, 2H), 2.46 (s,2H), 2.30 (s, 3H), 2.32-2.2 (m, 2H), 2.10-1.75 (m, 4H), 0.50 (m, 4H) 2543-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propan-1-ol ¹H NMR: 7.96 (d, 1H), 7.87 (d,1H), 7.57 (s, 1H), 7.46-7.24 (m, 5H), 5.88 (s, 1H), 3.8-3.65 (m, 3H),3.28-3.15 (m, 1H), 3.07-2.97 (m, 1H), 2.87-2.70 (m, 2H), 2.34 (s, 3H),2.45-2.25 (m, 2H), 2.20-1.75 (m, 7H) 2551-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propan-2-ol ¹H NMR: 8.06 (d, 1H), 7.91 (d,1H), 7.46-7.24 (m, 6H), 6.09 (s, 1H), 5.5-4.0 (sl, 1H), 3.85-3.70 (m,2H), 3.28-3.07 (m, 2H), 3.07-2.85 (m, 4H), 2.63 (s, 3H), 2.18-1.70 (m,4H), 1.11 (d, 3H) 2564-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butan-1-ol ¹H NMR: 7.97 (d, 1H), 7.87 (d, 1H), 7.50-7.24 (m, 6H), 5.88 (s,1H), 3.77-3.60 (m, 3H), 3.00-2.90 (m, 2H), 2.85-2.70 (m, 2H), 2.33 (s,3H), 2.41-2.20 (m, 2H), 2.20-1.60 (m, 9H)

Example 1502-[(3-benzylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole

A screw-cap tube is charged with2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole(200 mg), palladium bis(dibenzylideneacetone) (14 mg), Xantphos (14 mg),benzyl mercaptan (59 μL), Diisopropylethylamine (174 μL) and 1,4-dioxane(2 mL). The tube is evacuated, filled with argon and sealed. Afterstirring at 120° C. for 24 h, the mixture is diluted with ethyl acetateand water and the aqueous phase is extracted with ethyl acetate. Thepooled organic extracts are dried over magnesium sulfate andconcentrated under reduced pressure. The residue is purified bychromatography (gradient dichloromethane/methanol/ammonia from 100/0/0to 95/5/0.5) to afford2-[(3-benzylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole

¹H NMR: 12.38 (sl, 1H), 7.55 (d, 1H), 7.50-7.40 (m, 2H), 7.30-7.00 (m,10H), 5.84 (s, 1H), 4.20 (s, 2H), 3.65-3.45 (m, 1H), 3.20-3.00 (m, 2H),2.90-2.60 (m, 2H), 2.57 (s, 3H), 2.00-1.60 (m, 4H)

Further examples can be prepared according to the above describedgeneral method:

Example Product 1532-[(3-ethylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole¹H NMR: 7.54 (sl, 1H), 7.40 (s, 1H), 7.27-7.17 (m, 6H), 5.82 (s, 1H),3.65-3.50 (m, 1H), 2.87 (q, 2H), 2.80-2.60 (m, 2H), 2.23 (s, 3H),2.20-1.65 (m, 6H), 1.23 (s, 3H) 154{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetic acid methyl ester ¹H NMR: 9.66 (sl,1H), 7.90-7.20 (m, 8H), 5.84 (s, 1H), 3.71-3.50 (m, 6H), 2.80-2.60 (m,2H), 2.28 (s, 3H), 2.27-1.65 (m, 6H) 1572-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanol ¹H NMR: 9.76 (sl, 1H), 7.72 (s,1H),7.52 (s, 1H), 7.42 (s, 1H) 7.30-7.15 (m, 5H), 5.84 (s, 1H), 3.74 (t,2H), 3.57-3.51 (m, 1H), 3.10 (t, 2H), 2.75-2.55 (m, 2H), 2.24 (s, 3H),2.10-1.60 (m, 7H) 1732-[[3-(furan-2-ylmethylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole ¹H NMR: 12.36 (sl, 1H), 7.54-7.44 (m, 4H), 7.26 (m, 3H),7.18-7.10 (m, 2H), 6.22-6.15 (m, 2H), 5.83 (s, 1H), 4.20 (s, 2H),3.35-3.50 (m, 1H), 3.0-2.8 (m, 2H), 2.36 (s, 3H), 2.0-1.8 (m, 2H),1.8-1.6 (m, 2H), 1.25-1.05 (m, 2H) 2022-[(1-methylpiperidin-4-yloxy)(3-methylsulfanyl-phenyl)methyl]-1H-benzimidazole ¹H NMR: 7.65-7.52 (m, 2H), 7.36 (s, 1H), 7.30-7.10 (m,5H), 5.85 (s, 1H), 3.97-3.85 (m, 1H), 3.47-3.30 (m, 2H), 3.20-2.90 (m,2H), 2.69 (s, 3H), 2.43 (s, 3H), 2.38-2.0 (m, 4H) 2152-[(3-tert-butylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole ¹H NMR: 9.51 (sl, 1H), 7.67 (s, 1H), 7.55-7.40 (m, 4H),7.38-7.20 (m, 3H), 5.88 (s, 1H), 3.70-3.55 (m, 1H), 2.85-2.70 (m, 2H),2.29 (s, 3H), 2.28-2.10 (m, 2H), 2.05-1.70 (m, 4H), 1.25 (s, 9H) 2322-{(1-methylpiperidin-4-yloxy)[3-(2-pyrazin-2-yl-ethylsulfanyl)phenyl]methyl}-1H-benzimidazole ¹H NMR: 10.24 (sl, 1H), 8.48 (m, 1H), 8.41 (m, 2H),7.73 (sl, 1H), 7.51 (s, 1H), 7.33 (sl, 1H) 7.27-7.15 (m, 5H), 5.85 (s,1H), 3.70-3.60 (m, 1H), 3.34 (t, 2H), 3.09 (t, 2H), 1.60-1.80 (m, 2H),2.23 (s, 3H), 2.23-1.60 (m, 6H) 2484-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butan-1-ol ¹H NMR: 10.04 (sl, 1H), 7.88-7.35(m, 3H), 7.30-7.15 (m, 5H), 5.83 (s, 1H), 3.75-3.62 (m, 2H), 3.62-3.58(m, 1H), 2.92 (t, 2H), 2.85-2.65 (m, 2H), 2.27 (s, 3H), 2.20-2.05 (m,2H), 2.05-1.6 (m, 9H) 2883-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propane-1,2-diol ¹H NMR: 12.38 (sl, 1H),7.52 (d, 1H), 7.40-7.40 (m, 2H) 7.30-7.0.4 (m, 5H), 5.83 (s, 1H),5.00-4.3 (m, 3H), 3.80-4.10 (m, 4H), 2.90-2.70 (m, 2H), 2.50-2.33 (m,1H), 2.33 (s, 3H), 2.00-1.80 (m, 2H), 1.70-1.50 (m, 2H) 2956-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}hexan-1-ol ¹H NMR: 10.08 (sl, 1H), 7.85-7.60(m, 1H), 7.43 (sl, 2H), 7.32-7.15 (m, 5H), 5.84 (s, 1H), 3.70-3.50 (m,3H), 2.92-2.65 (m, 4H), 2.28 (s, 3H), 2.20-1.30 (m, 14H)

Example 165 165A5,6-dichloro-2-[(1-methylpiperidin-4-yloxy)phenylmethyl]-1H-benzimidazole

A round-bottom flask is charged with 4,5-dichlorobenzene-1,2-diamine(354 mg) and toluene (2 mL); a solution of trimethylaluminum 2M intoluene (1 mL) is added dropwise. The reaction mixture is heated at 60°C. for one hour. A solution of (1-methyl-piperidin-4-yloxy)phenylaceticacid ethyl ester in toluene (1 mL) is added dropwise and heating ispursued for one hour. The reaction mixture is cooled to room-temperatureand a solution of sodium hydroxide is added dropwise to pH 10. Theslurry is filtered on celite, cake washed with water (4×5 mL) and ethylacetate (4×5 mL). After decantation, the aqueous phase is extracted withethyl acetate. The pooled organic extracts are washed with brine, driedover magnesium sulfate and concentrated under reduced pressure. Theresidue is diluted with glacial acetic acid (3 mL) and the reactionmixture is heated at reflux for one hour. Acetic acid is removed on arotary evaporator and the residue is purified by chromatography(gradient dichloromethane/methanol/ammonia from 98/2/0 to 95/5/0.5 togive5,6-dichloro-2-[(1-methylpiperidin-4-yloxy)phenylmethyl]-1H-benzimidazolemelting at 221° C.

165B (1-Methylpiperidin-4-yloxy)phenylacetic acid ethyl ester

To a solution of4-(Ethoxycarbonyl-phenyl-methoxy)-piperidine-1-carboxylic acidtert-butyl ester (3.4 g) in dichloromethane (25 mL) is addedtrifluoroacetic acid (18 mL). After 30 minutes at room temperature, thevolatiles are removed under reduced pressure. Water (30 mL) is added andthe solution is basified by adding a solution of saturated sodiumcarbonate to pH 10. The aqueous phase is extracted with dichloromethane.The pooled organic extracts are dried over magnesium sulfate andconcentrated under reduced pressure to give(1-methylpiperidin-4-yloxy)phenylacetic acid ethyl ester used withoutfurther purification.

165C

(1-Methylpiperidin-4-yloxy)phenylacetic acid ethyl ester obtained aboveis dissolved in 1,4-dioxane (40 mL) and 40% aqueous solution offormaldehyde (4 mL) as well as a 1 molar solution of sodiumhypophosphorous acid (46 mL); The reaction mixture is heated to 80° C.overnight. 1,4-dioxane is removed under reduced pressure and theresidual solution is basified by adding a solution of saturated sodiumcarbonate to pH 10. The aqueous phase is extracted with ethyl acetate.The pooled organic extracts are dried over magnesium sulfate andconcentrated under reduced pressure. The residue is purified bychromatography (gradient dichloromethane/methanol/ammonia from 98/2/0.2to 95/5/0.5) to afford (1-methylpiperidin-4-yloxy)phenylacetic acidethyl ester.

¹H NMR: 7.50-7.45 (m, 2H), 7.38-7.20 (m, 3H), 5.00 (s, 1H), 4.18 (q,2H), 3.55-3.40 (m, 1H), 2.83-2.65 (m, 2H), 2.28 (s, 3H), 2.25-2.08 (m,2H), 2.05-1.65 (m, 4H), 1.22 (t, 3H)

165D 4-(Ethoxycarbonylphenylmethoxy)piperidine-1-carboxylic acidtert-butyl ester

To a solution of diazophenylacetic acid ethyl ester (2.55 g) in1,2-dichloroethane is added 4-hydroxypiperidine-1-carboxylic acidtert-butyl ester (5.4 g). The flask is evacuated and filled with argon.Rhodium(II) acetate-dimer (60 mg) is added to the reaction mixture.Evolution of nitrogen occurs until the end of the reaction (about 1hour). The solvent is removed under reduced pressure. The residue ispurified by chromatography (gradient heptane/ethyl acetate from 95/5 to80/20) to give 4-(ethoxy-carbonylphenylmethoxy)piperidine-1-carboxylicacid tert-butyl ester.

¹H NMR: 7.52-7.28 (m, 5H), 5.01 (s, 1H), 4.15 (q, 2H), 3.90-3.70 (m,2H), 3.68-3.55 (m, 1H), 3.18-3.00 (m, 2H), 2.00-1.50 (m, 4H), 1.44 (s,9H), 1.26 (t, 3H)

165E Diazophenylacetic Acid Ethyl Ester

To a solution of ethyl phenylacetate (3.28 g) in acetonitrile (60 mL) isadded para-toluenesulfonylazide (4.53 g). The reaction mixture is cooledto 0° C. and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.9 mL) is addeddropwise. The reaction mixture is kept at 5° C. overnight. Solvent isremoved to dryness and the residue is purified by chromatography(gradient petroleum ether/dichloromethane from 90/10 to 80/20) to givediazophenylacetic acid ethyl ester;

¹H NMR: 7.48-7.58 (m, 2H), 7.45-7.30 (m, 2H), 7.22-7.10 (m, 1H), 4.35(q, 2H), 1.30 (t, 3H)

Example 1723-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzonitrile

To a solution of2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole (200mg) in N,N-dimethylformamide (2.5 mL) and water (0.2 mL) are addedcopper(I) cyanide (180 mg), bis(dibenzylidenacetone)palladium (14.3 mg)and Xantphos (14.4 mg). The tube is evacuated, filled with argon andsealed. After stirring at 120° C. for 48 h, the mixture is diluted withwater then extracted with ethyl acetate. The pooled organic extracts arewashed with water, brine, dried over magnesium sulfate and concentratedunder reduced pressure. The residue is purified by chromatography(gradient dichloromethane/methanol/ammonia from 100/0/0 to92.5/7.5/0.75) to afford3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzonitrile

¹H NMR: 9.75 (sl, 1H), 7.82 (s, 1H), 7.80-7.62 (m, 2H), 7.57 (d, 1H),7.50-7.20 (m, 4H), 5.89 (s, 1H), 3.60-3.40 (m, 1H), 2.75-2.55 (m, 2H),2.25 (s, 3H), 2.20-1.60 (m, 6H)

Example 188

4-[benzothiazol-2-yl(3-bromo-phenyl)methoxy]-1,1-dimethylpiperidinium

To a solution of2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole (100mg) in acetonitrile is added iodomethane (1 molar equivalent) and thereaction mixture is refluxed for 1 hour. Solvent is removed underreduced pressure to dryness, the residue is triturated withdiethylether, filtered, the cake is washed with diethylether and driedto give4-[benzothiazol-2-yl(3-bromo-phenyl)methoxy]-1,1-dimethylpiperidiniummelting at 95° C.

Example 1892-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)isoindole-1,3-dione

A screw-cap tube is charged with2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole(200 mg), dichloro-bis(triphenylphosphine) palladium(II) (9.2 mg),copper(I) iodide (16.4 mg), N-propargylphthalimide (400 mg),diethylamine (310 μL) and N,N-dimethylformamide (2 mL). The tube isevacuated, filled with argon and sealed. After stirring atroom-temperature for 24 h, the mixture is diluted with water and theaqueous phase is extracted with ethyl acetate. The pooled organicextracts are washed with water, dried over magnesium sulfate andconcentrated under reduced pressure. The residue is purified bychromatography (gradient dichloromethane/methanol/ammonia from 98/2/0.2to 95/5/0.5 to give2-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)isoindole-1,3-dione.

¹H NMR: 9.52 (sl, 1H), 7.91-7.15 (m, 12H), 5.81 (s, 1H), 4.66 (s, 2H),3.65-3.55 (m, 1H), 2.85-2.65 (m, 2H), 2.28 (s, 3H), 2.30-2.05 (m, 2H),2.05-1.60 (m, 4H)

Following compounds are prepared analogously:

Example Product 2273-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-yn-1-ol¹H NMR: 7.96 (d, 1H), 7.85 (d, 1H), 7.51 (s, 1H), 7.55-7.23 (m, 5H),5.89 (s, 1H), 4.46 (s, 2H), 3.70-3.55 (m, 1H), 2.78-2.62 (m, 2H), 2.27(s, 3H), 2.27-2.08 (m, 2H), 2.05-1.70 (m, 4H) 2364-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-yn-1-ol¹H NMR: 7.97 (d, 1H), 7.87 (d, 1H), 7.58 (s, 1H), 7.47-7.27 (m, 5H),5.87 (s, 1H), 3.88-3.65 (m, 3H), 2.95-2.80 (m, 2H), 2.67 (t, 2H), 2.39(s, 3H), 2.45-2.30 (m, 2H), 2.18 (s, 1H), 2.17-1.80 (m, 4H) 2375-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-yn-1-olhydrochloride ¹H NMR (DMSO-d⁶): 9.79 (sl, 1H), 8.07 (d, 1H), 7.92 (d,1H), 7.50-7.30 (m, 5H), 6.12 (d, 1H), 3.92-3.70 (m, 1H), 3.50-2.95 (m,6H), 2.76 and 2.67 (d, 3H), 2.48-2.35 (m, 2H), 2.30 1.60 (m, 6H)

Example 1943-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynylamine194A

A solution of2-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-phenyl}prop-2-ynyl)isoindole-1,3-dione(70 mg) and hydrazine hydrate (70 μL) in ethanol (0.7 mL) is stirred aroom temperature for 3 hours. Ethanol is removed under reduced pressureand 1N hydrochloric acid in water is added to the organic residue andstirred for 5 minutes. The mixture is filtered, cake washed with ethylacetate. The filtrate is extracted by dichloromethane. The pooledorganic extracts are dried over magnesium sulfate and concentrated underreduced pressure The residue purified by chromatography(dichloromethane/methanol/ammonia from 90/10/1) to afford3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynylaminemelting at 101° C.

194B

2-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)isoindole-1,3-dioneis prepared according to general procedure 189.

Following compounds are prepared analogously:

Example Product 2824-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynylamine ¹H NMR: 7.98 (d, 1H), 7.88 (d, 1H), 7.58 (s, 1H), 7.52-7.25(m, 5H), 5.86 (s, 1H), 3.82-3.68 (m, 1H), 2.95-2.70 (m, 2H), 2.68-2.50(m, 4H), 2.47 (s, 3H), 2.40-1.75 (m, 6H) 2864-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynylamine ¹H NMR: 9.50 (sl, 1H), 7.72 (sl, 1H), 7.55-7.20 (m, 7H), 5.84(s, 1H), 3.65-3.55 (m, 1H), 2.91 (t, 2H), 2.80-2.65 (m, 2H), 2.54 (t,2H), 2.26 (s, 3H), 2.18-1.60 (m, 6H) 287e5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine ¹H NMR: 7.97 (d, 1H), 7.87 (d, 1H), 7.56 (s, 1H), 7.46-7.24(m, 5H), 5.87 (s, 1H), 3.71-3.56 (m, 1H), 2.95-2.82 (m, 2H), 2.82-2.66(m, 2H), 2.47 (t, 2H), 2.29 (s, 3H), 2.28-2.18 (m, 2H), 2.10-1.70 (m,8H) 3376-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynylamine ¹H NMR: 7.70-7.45 (m, 3H), 7.40-7.10 (m, 5H), 5.84 (s, 1H),3.60-3.55 (m, 2H), 3.32-3.17 (m, 1H), 2.80-2.60 (m, 4H), 2.45-2.30 (m,2H), 2.24 (s, 3H), 2.18-1.50 (m, 10H)

Example 1952-[(3-ethynylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole195A

To a solution of2-[(3-trimethylsilylethynylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole(205 mg) in methanol (2 mL) is added potassium carbonate (81 mg). Thereaction mixture is stirred at room temperature for 4 hours, thenmethanol is removed under reduced pressure. The residue is dissolved inwater and extracted with ethyl acetate. The organic phase is dried onmagnesium sulphate and solvent is removed under reduced pressure to give2-[(3-ethynylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole

¹H NMR: 9.42 (sl, 1H), 7.80-7.70 (m, 1H), 7.62 (s, 1H), 7.48-7.36 (m,3H) 7.34-7.20 (m, 3H), 5.86 (s, 1H), 3.65-3.48 (m, 1H), 3.07 (s, 1H),2.78-2.65 (m, 2H), 2.25 (s, 3H), 2.20-1.60 (m, 6H)

195B

2-[(3-trimethylsilylethynylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazolecan be obtained using general method described in example 189.

Example 1982-{(1-methylpiperidin-4-yloxy)[3-(1H-[1,2,3]triazol-4-yl)phenyl]methyl}-1H-benzimidazole

To a solution of2-[(3-(ethynylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole(110 mg) in methanol (2 mL) and N,N-dimethylformamide (0.7 mL) in ascrew-cap tube is added L). The reaction mixture□copper(I) iodide (3.2mg) and azidotrimethylsilane (56 is heated at 100° C. overnight, thensolvents are removed under reduced pressure. The residue is dissolved inwater and ammonia solution is added to pH10; the aqueous phase isextracted with dichloromethane. The organic phase is dried on magnesiumsulphate and solvent is removed under reduced pressure to give2-{(1-methylpiperidin-4-yloxy)[3-(1H-[1,2,3]triazol-4-yl)phenyl]methyl}-1H-benzimidazole.

¹H NMR: 7.98 (s, 1H), 7.86 (s, 1H), 7.80-7.50 (m, 3H), 7.48-7.30 (m,2H), 7.29-7.15 (m, 2H), 5.95 (s, 1H), 3.68-3.50 (m, 1H), 2.96-2.89 (m,1H), 2.85-2.65 (m, 2H), 2.26 (s, 3H), 2.20-1.70 (m, 6H)

Example 1993-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]benzoic acidmethyl ester, oxalate

A solution of3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]benzonitrile (109mg, example 197) in methanol (5 mL) is treated with a flow of hydrogenchloride while refluxing for 4 h. After stirring at room temperature forone night, the mixture is concentrated under reduced pressure and theresidue purified over silica gel (dichloromethane/methanol/ammonia95/5/0.5) to afford3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]benzoic acidmethyl ester which is then converted into its oxalate salt in acetone togive 3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]benzoic acidmethyl ester, oxalate melting at 93° C.

Example 2002-[(1-methylpiperidin-4-yloxy)phenyl-methyl]-3H-benzimidazol-4-ylamine

To a solution of DMF (44 mg) in L). As soon as □1,2-dichloroethane (2.5mL) is added dropwise oxalylchloride (51 the gas evolution ceased, thevolatiles are removed under reduced pressure. To the residue are added1,2-dichloroethane (2.5 mL) and (1-methylpiperidin-4-yloxy)phenylaceticacid (125 mg). The reaction mixture is stirred at room temperature for 1hour, then 1,2-diamino-3-nitrobenzene is added and the mixture isstirred overnight. Water is added and the solution is basified by addinga solution of saturated sodium carbonate to pH 10. The aqueous phase isextracted with ethyl acetate. The pooled organic extracts are dried overmagnesium sulfate and concentrated under reduced pressure. The residueis purified by chromatography (gradient dichloromethane/methanol/ammoniafrom 98/2/0.2 to 95/5/0.5).

To the residual solid in ethanol (4.5 mL) is added tin(II)dichloride.The reaction mixture is refluxed for 2 hours. The solution is basifiedby adding a solution of 10N sodium hydroxide to pH 6. The aqueous phaseis extracted with chloroform. The pooled organic extracts are dried overmagnesium sulfate and concentrated under reduced pressure. The residueis dissolved in acetic acid and the reaction mixture is refluxed for 3hours. Acetic acid is removed, methanol (1 mL) and 12N hydrochloric acidare added to the residue. The reaction mixture is heated to 60° C. for 1hour.

The solution is basified by adding a solution of saturated sodiumcarbonate to pH 10. The aqueous phase is extracted with ethyl acetate.The pooled organic extracts are dried over magnesium sulfate andconcentrated under reduced pressure. The residue is purified bychromatography (gradient dichloromethane/methanol/ammonia from 98/2/0.2to 90/10/1) to afford2-[(1-methylpiperidin-4-yloxy)phenyl-methyl]-3H-benzimidazol-4-ylaminemelting at 96.7° C.

Example 2032-[(3-methanesulfonylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole

To a solution of2-[(1-methylpiperidin-4-yloxy)(3-methylsulfanylphenyl)methyl]-benzothiazole(100 mg) in methanol (2 mL) and water (1 mL) at 0° C. is addedportionwise Oxone® (400 mg) over 1 hour.

The mixture is diluted with water. The aqueous phase is extracted withethyl acetate. The pooled organic extracts are washed with water, driedover magnesium sulfate and concentrated under reduced pressure. Theresidue is purified by chromatography (gradient dichloromethane/methanolfrom 98/2 to 90/10) to afford2-[(3-methanesulfonylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole.

¹H NMR: 8.17 (s, 1H), 7.97 (d, 1H), 7.90-7.83 (m, 3H), 7.60-7.39 (m,3H), 6.00 (s, 1H), 3.72-3.60 (m, 1H), 3.06 (s, 3H), 2.82-2.75 (m, 2H),2.28 (s, 3H), 2.28-2.10 (m, 2H), 2.05-1.70 (m, 4H)

Example 2063-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]benzoic acid ethylester, oxalate

3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]benzoic acid ethylester, oxalate melting at 104° C. can be prepared as described inexample 199.

Example 207{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}methanol,oxalate

A solution of3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]benzoic acid ethylester (0.55 g, example 206) in tetrahydrofurane (10 mL) is treated withlithium aluminum hydride (76 mg) at room temperature for 1 h. Two otheradditions of lithium aluminum hydride (76 mg each) allow a completeconversion. The mixture is then hydrolyzed with water (178 μL), 5%sodium hydroxide (178 μL) and water (535 μL), filtered through a pad ofclarcel and concentrated under reduced pressure. The residue is purifiedover silica gel (dichloromethane/methanol/ammonia 95/5/0.5) to afford{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}methanolwhich is then converted into its oxalate salt in acetone to give{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}methanol,oxalate.

¹H NMR (DMSO-d6): 8.06 (d, 1H), 7.90 (d, 1H), 7.50-7.20 (m, 6H), 6.09(s, 1H), 4.47 (s, 2H), 3.75 (m, 1H), 3.16 (m, 2H), 2.98 (m, 2H), 2.64(s, 3H), 2.10-1.75 (m, 4H).

Example 2083-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}propionicacid tert-butyl ester

A screw-cap tube is charged with2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole (208mg), palladium(II) acetate (3 mg), RuPhos® (12 mg), potassium3-trifluoroboratopropionate tert-butyl ester (118 mg), potassiumcarbonate (207 mg), water (2.5 mL) and toluene (2.5 mL). The tube isevacuated, filled with argon and sealed. After stirring at 120° C.overnight, the mixture is diluted with ethyl acetate and water and theaqueous phase is extracted with ethyl acetate. The pooled organicextracts are dried over magnesium sulfate and concentrated under reducedpressure. The residue is purified by chromatography (gradientdichloromethane/methanol from 100/0 to 95/5) to afford3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}propionicacid tert-butyl ester.

¹H NMR: 7.97 (d, 1H), 7.86 (s, 1H), 7.45-7.22 (m, 5H), 7.12 (d, 1H),5.89 (s, 1H), 3.72-3.58 (m, 1H), 2.87 (t, 2H), 2.78-2.65 (m, 2H), 2.53(t, 2H), 2.29 (s, 3H), 2.28-2.10 (m, 2H), 2.08-1.72 (m, 4H), 1.39 (s,9H)

Example 2102-[(1-methylpiperidin-4-yloxy)phenylmethyl]-3H-benzimidazol-4-ol

To a solution of (1-methylpiperidin-4-yloxy)phenylacetic acid (250 mg)in acetonitrile (5 mL) are added 2,3-diaminophenol (125 mg),2-chloro-1-methylpyridinium iodide (255 mg) and dropwisediisopropylethylamine (0.44 mL). The reaction mixture is stirred at roomtemperature for 3 hours. Solvent is removed under reduced pressure.Water is added to the residue and the solution is basified by adding asolution of saturated sodium carbonate to pH 10. The aqueous phase isextracted with ethyl acetate. The pooled organic extracts are dried overmagnesium sulfate and concentrated under reduced pressure. The residueis purified by chromatography (gradient dichloromethane/methanol/ammoniafrom 98/2/0.2 to 90/10/1).

The residue is dissolved in acetic acid (2 mL) and the reaction mixtureis refluxed for 24 hours. Acetic acid is removed under reduced pressure.Water is added to the residue and the solution is basified by adding asolution of saturated sodium carbonate to pH 10. The aqueous phase isextracted with ethyl acetate. The pooled organic extracts are dried overmagnesium sulfate and concentrated under reduced pressure. The residueis purified by chromatography (gradient dichloromethane/methanol/ammoniafrom 98/2/0.2 to 90/10/1). The residual solid is re-crystallized fromhot toluene to give2-[(1-methylpiperidin-4-yloxy)phenylmethyl]-3H-benzimidazol-4-ol meltingat 170.5° C.

Example 211[benzothiazol-2-yl(4′-methoxybiphenyl-3-yl)methyl](1-methylpiperidin-4-yl)amine,dioxalate 211A

[benzothiazol-2-yl(4′-methoxybiphenyl-3-yl)methyl](1-methylpiperidin-4-yl)amine,dioxalate melting at 130° C. can be prepared according to generalprocedure 91A from benzothiazol-2-yl(4′-methoxybiphenyl-3-yl)methanol.

211B

A mixture of benzothiazol-2-yl(3-bromophenyl)methanol (200 mg),4-methoxy-phenylboronic acid (142 mg),tetrakis(triphenylphosphine)palladium (50 mg), potassium carbonate (259mg), water (4 mL), ethanol (1 mL) and toluene (9 mL) is purged withargon and refluxed for one night. After cooling at room temperature, themixture is diluted with water and diethylether. The organic phase isdried over magnesium sulfate and concentrated under reduced pressure.The residue is purified by column chromatography (heptane/ethyl acetate2/1) to afford benzothiazol-2-yl(4′-methoxybiphenyl-3-yl)methanol as abeige solid.

Example 2173-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}acrylonitrile

To a solution of2-[(3-Iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzimidazole (230mg) in tetrahydrofuran (2.5 mL) in a screw-capped tube are addedacrylonitrile (0.15 mL), triethylamine (2.5 mL) andtetrakis(triphenylphosphine)palladium. The tube is evacuated, filledwith argon, sealed and heated at 70° C. for 18 h. Solvent and volatilesare removed under reduced pressure and the residue is purified bychromatography (gradient dichloromethane/methanol/ammonia from 100/0/0to 95/5/0.5 to give3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}acrylonitrile.

¹H NMR: 7.98 (d, 1H), 7.88 (d, 1H), 7.65-7.55 (m, 2H), 7.55-7.35 (m,5H), 5.92 (d, 1H), 5.88 (s, 1H), 4.00-3.90 (m, 1H), 3.25-2.95 (m, 4H),2.65 (s, 3H), 2.50-2.35 (m, 2H), 2.25-2.00 (m, 2H)

Following compounds are prepared analogously:

Example Product 2053-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}acrylicacid tert-butyl ester ¹H NMR: 7.98 (d, 1H), 7.87 (s, 1H), 7.68 (s, 1H),7.60-7.36 (m, 6H), 6.37 (d, 1H), 5.93 (s, 1H), 3.72-3.59 (m, 1H),2.80-2.65 (m, 2H), 2.29 (s, 3H), 2.28-2.10 (m, 2H), 2.05-1.60 (m, 4H),1.74 (s, 9H). 2092-[[3-(2-benzenesulfonylvinyl)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole ¹H NMR: 8.02-7.92 (m, 3H), 7.98 (d, 1H),7.75-7.35 (m, 9H), 7.30-7.15 (m, 1H), 6.90 (d, 1H), 5.88 (s, 1H),4.10-3.95 (m, 1H), 3.45-3.25 (m, 4H), 2.76 (s, 3H), 2.70-2.45 (m, 2H),2.35-2.10 (m, 2H) 2122-[[3-(2-methanesulfonylvinyl)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole ¹H NMR: 7.99 (d, 1H), 7.88 (s, 1H), 7.78-7.59(m, 3H), 7.55-7.38 (m, 4H), 6.92 (d, 1H), 5.94 (s, 1H), 3.78-3.62 (m,1H), 3.03 (s, 3H), 2.87-2.70 (m, 2H), 2.32 (s, 3H), 2.40-2.13 (m, 2H),2.10-1.75 (m, 4H)

Example 2193-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]-N-benzyl-N-methylbenzamide

A screw-capped tube is charged with2-[(3-bromo-phenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole(example 27, 400 mg), N-benzylmethylamine (178 μL),1,8-diazabicyclo(5.4.0)undec-7-ene (100 μL),trans-di-μ-acetatobis[2-(di-o-tolyl-phosphino)benzyl]dipalladium(II) (22mg), tri-tert-butylphosphonium tetrafluoroborate (17 mg), molybdenumhexacarbonyl (127 mg) and tetrahydrofurane (3 mL). The tube is sealedand heated at 125° C. for 10 min. The reaction was allowed to cool toroom temperature and concentrated under reduced pressure. The residue ispurified over silica gel (gradient dichloromethane/methanol/ammonia from98/2/0.5 to 95/5/0.5) to afford3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]-N-benzyl-N-methylbenzamidewhich is then converted into its oxalate salt in acetone to give3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]-N-benzyl-N-methylbenzamide,oxalate melting at 103° C.

Example 2243-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylamine224A

To a solution of2-[(1-methylpiperidin-4-yloxy)(3-nitrophenyl)methyl]-1H-benzimidazole(110 mg) in ethanol is added tin(II)dichloride (340 mg). The reactionmixture is refluxed for 2 hours. The solution is basified by adding asolution of 10N sodium hydroxide to pH 10. The aqueous phase isextracted with chloroform. The pooled organic extracts are dried overmagnesium sulfate and concentrated under reduced pressure. The residueis purified by chromatography (gradient dichloromethane/methanol/ammoniafrom 98/2/0.2 to 90/10/1) to give3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylaminemelting at 100° C.

224 B

2-[(1-Methylpiperidin-4-yloxy)(3-nitrophenyl)methyl]-1H-benzimidazolecan be prepared according to the method described in example 165.

Example 2283-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxymethyl}-phenylamine,oxalate

A suspension of2-{(1-methylpiperidin-4-yloxy)[3-(3-nitro-benzyloxy)phenyl]-methyl}benzothiazole(example 196, 55 mg) and tin(II) chloride dihydrate (250 mg) in ethanol(2 mL) is refluxed for 1 h. The cooled mixture is diluted withdichloromethane and aqueous 1N sodium hydroxide. The organic phase isdried over magnesium sulfate and concentrated under reduced pressure toafford3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxymethyl}-phenylaminewhich is then converted into its oxalate salt in acetone to give3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxymethyl}-phenylamine,oxalate as an orange solid. TLC of the base (eluent: CH₂Cl₂/MeOH/NH₄OH95/5/0.5): Rf=0.14.

Example 2292-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanolenantiomer A

A solution of racemic2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanol(10 mg/mL) in a mixture of heptane/isopropanol (75/25) containingdiethylamine (0.1%) is injected (20×100 μL) onto an analytical ChiralcelOD-H, 250×4.6 mm column. Elution is performed with a mixture ofheptane/isopropanol (80/20) containing diethylamine (0.1%) at a flow of1 mL/min. Products are detected at 220 nm.

The first enantiomer has a retention time of 7.0 min.

Collection affords2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanolenantiomer A with a chromatographic enantiomeric purity of 100.0%.

Example 2302-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanolenantiomer B

The second enantiomer has a retention time of 9.4 min.

Collection affords2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanolenantiomer B with a chromatographic enantiomeric purity of 97.8%.

Example 2312-[(3-azidophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole231A

To a solution of3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-phenylamine(57 mg) in methanol (3 mL) are added at 0° C. copper(II) sulphate and asolution of trifluoromethanesulfonylazide (freshly prepared from sodiumazide (220 mg) and trifluoromethanesulfonic anhydride (200 mg)) indichloromethane.

The reaction mixture is stirred overnight at 4° C. Volatiles are removedunder reduced pressure. Water is added to the residue and the solutionis basified by adding a solution of saturated sodium carbonate to pH 10.The aqueous phase is extracted with dichloromethane. The pooled organicextracts are dried over magnesium sulfate and concentrated under reducedpressure. The residue is purified by chromatography (gradientdichloromethane/methanol/ammonia from 98/2/0.2 to 90/10/1) to give2-[(3-azidophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazolemelting at 53° C.

231B

To a solution of2-[(1-Methyl-piperidin-4-yloxy)-(3-nitro-phenyl)-methyl]-1Hbenzimidazole(110 mg) in ethanol (5 mL) is added Tin(II)dichloride-dihydrate (340mg). The reaction mixture is heated at reflux for 2 hours. Water isadded to the mixture as well as sodium hydroxide 1N solution to pH 10.The solution is extracted with chloroform. The pooled organic phases aredried with magnesium sulphate and concentrated under reduced pressure.The residue is purified by chromatography (gradientdichloromethane/methanol/ammonia from 98/2/0.2 to 90/10/1) to give3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylaminethat is used without further purification.

Example 234{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}benzyl-amine,dioxalate

A screw-capped tube is charged with2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole(example 41, 190 mg), copper(I) iodide (4 mg), ethylene glycol (45 μL),potassium carbonate (173 mg), benzylamine (54 μL), and propan-2-ol (1mL). The tube is evacuated, filled with argon and sealed. After stirringat 80° C. for 15 h, the mixture is diluted with ethyl acetate and waterand the aqueous phase is extracted with ethyl acetate. The pooledorganic extracts are dried over magnesium sulfate and concentrated underreduced pressure. The residue is purified by chromatography (gradientdichloromethane/methanol/ammonia from 98/2/0.5 to 95/5/0.5). The base isconverted into its dioxalate salt in acetone to give{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}benzyl-amine,dioxalate melting at 75° C.

Example 2583-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}propan-1-ol,oxalate

A screw-capped tube is charged with2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole(example 41, 150 mg), copper(I) iodide (6.5 mg),3,4,7,8-tetramethyl-1,10-phenanthroline (16.3 mg), cesium carbonate (223mg), propan-1,3-diol (74 mg), ground 4 Å molecular sieves (80 mg) andtoluene (4 mL). The tube is evacuated, filled with argon and sealed.After stirring at 90° C. for 24 h, the mixture is diluted withdichloromethane, water and ammonia. After filtration and decantation,the aqueous phase is extracted with dichloromethane. The pooled organicextracts are dried over magnesium sulfate and concentrated under reducedpressure. The residue is purified by chromatography (gradientdichloromethane/methanol/ammonia from 98/2/0.5 to 95/5/0.5). The base isconverted into its oxalate salt in acetone to give3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}propan-1-ol,oxalate melting at 79° C.

Example 2402-{(1-methylpiperidin-4-yloxy)[3-(2-[1,2,3]triazol-2-yl-ethylsulfanyl)phenyl]-methyl}benzothiazole240A

To a solution of 1,2,3-triazole (36.5 mg) in N,N-dimethylformamide (1mL) is added a dispersion of sodium hydride 60% in mineral oil (1 molarequivalent). The reaction mixture is stirred at room temperature for 15minutes, then a solution of methanesulfonic acid2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylester (85 mg) in N,N-dimethylformamide (1 mL) is added. The reactionmixture is stirred at 60° C. overnight. Water is added and the aqueousphase is extracted by ethyl acetate. The organic phase is dried overmagnesium sulfate and concentrated under reduced pressure. The residueis purified by column chromatography (gradientdichloromethane/methanol/ammonia 100/0/0 to 90/10/1) to afford2-{(1-methylpiperidin-4-yloxy)[3-(2-[1,2,3]triazol-2-yl-ethylsulfanyl)phenyl]methyl}benzothiazole.

¹H NMR: 7.97 (d, 1H), 7.87 (d, 1H), 7.65-7.25 (m, 8H), 5.90 (s, 1H),4.62 (t, 2H), 3.75-3.60 (m, 1H), 3.44 (t, 2H), 2.82-2.65 (m, 2H), 2.29(s, 3H), 2.45-2.15 (m, 2H), 2.10-1.70 (m, 4H)

and

2-{(1-methylpiperidin-4-yloxy)[3-(2-[1,2,3]triazol-1-yl-ethylsulfanyl)phenyl]methyl}-benzothiazole

¹H NMR: 7.95 (d, 1H), 7.87 (d, 1H), 7.86 (s, 1H), 7.61 (s, 1H), 7.56 (s,1H), 7.51-7.25 (m, 5H), 5.90 (s, 1H), 4.52 (t, 2H), 3.75-3.60 (m, 1H),3.39 (t, 2H), 2.82-2.65 (m, 2H), 2.31 (s, 3H), 2.35-2.15 (m, 2H),2.08-1.70 (m, 4H).

240B Methanesulfonic acid2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylester

To a solution of 2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)-methyl]phenylsulfanyl}ethanol (400 mg) indichloromethane (5 mL) is added methanesulfonylchloride (1.25 molarequivalent) in dichloromethane (1.5 mL) and triethylamine (1.5 molarequivalent). The reaction mixture is stirred overnight at roomtemperature. Volatiles are removed under reduced pressure to dryness.Water is added and the aqueous phase is extracted by diethylether. Theorganic phase is dried over magnesium sulfate and concentrated. Theresidue is purified by column chromatography (dichloromethane/methanolfrom 98/2) to afford methanesulfonic acid2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylester that will be used without further purification.

Example 2452-[(1-methylpiperidin-4-yloxy)(3-vinyl-phenyl)methyl]-1H-benzimidazole

In a screw-cap tube are placed2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]benzimidazole (200mg), potassium vinyltrifluoroborate (72 mg),1,1-bis(diphenylphosphino)ferrocene-dichloro-palladium (7.5 mg) andn-propanol (3 mL). The reaction mixture is degassed and purged withargon. The mixture is heated at reflux for 48 h. Water and ammoniasolution are added and the aqueous phase is extracted by ethyl acetate.The organic phase is dried over magnesium sulfate and concentrated. Theresidue is purified by column chromatography (gradientdichloromethane/methanol from 95/5 to 90/10 thendichloromethane/methanol/ammonia 90/10/0.1) to give2-[(1-methylpiperidin-4-yloxy)(3-vinyl-phenyl)methyl]-1H-benzimidazole.

¹H NMR: 7.68-7.55 (m, 2H), 7.48 (s, 1H), 7.45-7.33 (m, 3H), 7.33-7.20(m, 2H), 6.65 (dd, 1H), 5.83 (s, 1H), 5.75 (d, 1H), 5.26 (d, 1H),3.88-3.75 (m, 1H), 3.28-3.10 (m, 2H), 3.05-2.75 (m, 2H), 2.63 (s, 3H),2.30-1.95 (m, 4H)

Example 2492-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-ethylamine249A

To a solution ofN-tert-butoxycarbonyl-2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylaminein dichloromethane (2 mL) is added trifluoroacetic acid (0.5 ml) at roomtemperature. The mixture is stirred at room temperature for 24 h. Wateris added and the mixture is basified by adding a solution of sodiumhydroxide. The aqueous phase is extracted by ethyl acetate. The organicphase is washed by water, then dried over magnesium sulfate andconcentrated. The residue is triturated in diisopropylether to give2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine.

¹H NMR: 7.80-7.65 (m, 1H), 7.51 (s, 1H), 7.48-7.15 (m, 7H), 5.85 (s,1H), 3.65-3.53 (m, 1H), 3.08-2.95 (m, 2H), 2.95-2.80 (m, 2H), 2.80-2.60(m, 2H), 2.25 (s, 3H), 2.18-1.62 (m, 6H)

249B

N-tert-butoxycarbonyl-2-{3[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylaminecould be prepared using method described in example 150A.

Example 2522-[(1-methylpiperidin-4-yloxy)-p-tolylmethyl]-1H-benzimidazoleenantiomer A

A solution of2-[(1-methylpiperidin-4-yloxy)-p-tolylmethyl]-1H-benzimidazole (10mg/mL) in methanol containing diethylamine (0.1%) is injected (17×100μL) onto an analytical Ceramospher chiral RU-1, 250×4.6 mm column.Elution is performed with a mixture of heptane/isopropanol (80/20)containing diethylamine (0.1%) at a flow of 1 mL/min. Products aredetected at 220 nm.

The first enantiomer has a retention time of 10.4 min.

Collection affords2-[(1-methylpiperidin-4-yloxy)-p-tolylmethyl]-1H-benzimidazoleenantiomer A with a chromatographic enantiomeric purity of 90%.

Example 2532-[(1-methylpiperidin-4-yloxy)-p-tolylmethyl]-1H-benzimidazoleenantiomer B

The second enantiomer has a retention time of 13.7 min.

Collection affords2-[(1-methylpiperidin-4-yloxy)-p-tolylmethyl]-1H-benzimidazoleenantiomer B with a chromatographic enantiomeric purity of 90%.

Example 2592-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-N-methylacetamide259A

To a solution of methylamine hydrochloride (76 mg) in toluene (2 mL) isadded a 2N solution of trimethylaluminum in toluene. The reactionmixture is heated at 60° C. for 1 hour. Then a solution of{3-[(benzothiazol-2-yl)(1-methylpiperidin-4-yloxy)-methyl]phenylsulfanyl}aceticacid methyl ester (50 mg) in toluene (1 mL) is added. The reactionmixture is heated at 60° C. for 24 hours. Water is added to the reactionmixture, pH is adjusted to 10 with a solution of sodium hydroxide, andthe mixture is filtered on celite. The filtrate is extracted with ethylacetate. The pooled organic extracts are dried over magnesium sulfateand concentrated under reduced pressure. The residue is purified bychromatography (toluene/acetone/triethylamine 80/20/0.2) to give2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-N-methylacetamide.

¹H NMR (DMSO-d⁶): 8.12-7.97 (m, 2H), 7.89 (d, 1H), 7.52-7.22 (m, 6H),5.90 (s, 1H), 3.60 (s, 2H), 3.59-3.45 (m, 1H), 2.62-2.40 (m, 5H), 2.03(s, 3H), 2.03-1.82 (m, 4H), 1.82-1.45 (m, 4H)

259B

{3-[(benzothiazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}aceticacid methyl ester can be obtained using method described in example 150.

Example 2602-{(1-methylpiperidin-4-yloxy)[3-(2H-pyrazol-3-yl)phenyl]methyl}benzothiazole260A

A solution of2-((1-Methyl-piperidin-4-yloxy)-{3-[2-(2-trimethylsilanyl-ethoxymethyl)-2H-pyrazol-3-yl]-phenyl}-methylybenzothiazole(500 mg) in 5N hydrochloric acid (4 mL) is stirred overnight at roomtemperature. 30% sodium hydroxide solution is added to reach pH 10, andthe reaction is diluted with water. The aqueous phase is extracted withethyl acetate. The pooled organic extracts are dried over magnesiumsulfate and concentrated under reduced pressure. The residue is purifiedby chromatography (gradient dichloromethane/methanol from 100/0 to90/10) to afford2-{(1-methylpiperidin-4-yloxy)[3-(2H-pyrazol-3-yl)phenyl]methyl}benzothiazolemelting at 90° C.

260B

2-((1-Methyl-piperidin-4-yloxy)-{3-[2-(2-trimethylsilanyl-ethoxymethyl)-2H-pyrazol-3-yl]-phenyl}-methyl)-benzothiazolecan be prepared according to the method described in example 53.

Example 264{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}aceticacid hydrazide

To a solution of{3-[(benzothiazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}aceticacid methyl ester (30 mg) in absolute ethanol (1 mL) is added hydrazinehydrate (0.1 mL). The reaction mixture is heated at 80° C. for 18 hours.Solvent and volatiles are removed under reduced pressure. The residue ispurified by chromatography (gradient dichloromethane/methanol from 95/5to 80/20) to give{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}aceticacid hydrazide.

¹H NMR (DMSO-d⁶): 10.30 and 10.15 (two singlets, 1H), 8.05 (d, 1H), 7.89(d, 1H), 7.50-7.20 (m, 6H), 5.99 (s, 1H), 3.89 (d, 2H), 3.58-3.45 (m,1H), 2.75-2.50 (m, 2H), 2.09 (s, 3H), 2.08-1.95 (m, 2H), 1.90-1.50 (m,6H)

Example 2682-(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}-cyclopropyl)ethanol268A

To a solution of1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}cyclopropanecarboxylicacid methyl ester (56 mg) in tetrahydrofuran (5 mL) is added lithiumaluminumhydride (25 mg) at 0° C. The reaction mixture is allowed toreach room temperature and ethyl acetate (2 mL) is added. After stirringfor 5 minutes, a half-saturated aqueous solution of sodium carbonate (6mL) is added. The aqueous phase is extracted with ethyl acetate. Thepooled organic extracts are dried over magnesium sulfate andconcentrated under reduced pressure. The residue is purified bychromatography (gradient dichloromethane/methanol/ammonia from 100/0/0to 95/5/0.5) to afford2-(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}cyclopropyl)ethanol.

¹H NMR: 7.97 (d, 1H), 7.87 (d, 1H), 7.56 (s, 1H), 7.52-7.22 (m, 5H),5.86 (s, 1H), 3.72 (t, 2H), 3.72-3.58 (m, 1H), 2.98 (dd, 2H), 2.82-2.78(m, 2H), 2.27 (s, 3H), 2.27-2.10 (m, 3H), 2.10-1.75 (m, 4H), 1.78 (t,2H), 0.44 (m, 4H)

268B

1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}-cyclopropanecarboxylicacid methyl ester can be obtained according to the method described inexample 150.

Further examples can be prepared according to the above describedgeneral method:

Example Product 2572-(1-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl-sulfanylmethyl}-cyclopropyl)ethanol ¹H NMR: 10.0 (sl, 1H), 7.60 (s, 1H),7.80-7.35 (m, 2H), 7.32-7.15 (m, 5H), 5.82 (s, 1H), 3.75 (t, 2H),3.68-3.50 (m, 1H), 3.01 (dd, 2H), 2.90-2.70 (m, 2H), 2.30 (s, 3H),2.27-2.10 (m, 2H), 2.10-1.75 (m, 5H), 1.67 (t, 2H), 0.45 (m, 4H)

Example 2751-(3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyloxy)-propan-2-one,oxalate

A screw-capped tube is charged with2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole(example 41, 300 mg), copper(I) iodide (10 mg), tetrakis palladium (36mg), triethylamine (0.33 mL), 1-methyl-2-pyrrolidinone (1.3 mL), and1-prop-2-ynyloxypropan-2-one (109 mg). The tube is evacuated, filledwith argon and sealed. After stirring at 80° C. for one night, themixture is diluted with ethyl acetate and water and the aqueous phase isextracted with ethyl acetate. The pooled organic extracts are dried overmagnesium sulfate and concentrated under reduced pressure. The residueis purified by chromatography (gradient dichloromethane/methanol/ammoniafrom 98/2/0.5 to 95/5/0.5). The base is converted into its oxalate saltin acetone to give1-(3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyloxy)-propan-2-one,oxalate. TLC of the base (eluent: CH₂Cl₂/MeOH/NH₄OH 95/5/0.5): Rf=0.18.

Example 2761-(3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyloxy)-propan-2-ol,oxalate

A solution of1-(3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyloxy)-propan-2-one(example 275, 140 mg) in methanol (20 mL) is treated with sodiumborohydride (30 mg) at 0° C., stirred 1 h at 0° C. and 2 h at roomtemperature. The mixture is then diluted with water and extracted withethyl acetate. The pooled organic extracts are dried over magnesiumsulfate and concentrated under reduced pressure. Purification of theresidue by chromatography (gradient dichloromethane/methanol/ammoniafrom 98/2/0.5 to 95/5/0.5) affords the pure base that is then convertedinto its oxalate salt in acetone to give1-(3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyloxy)-propan-2-ol,oxalate. TLC of the base (eluent: CH₂Cl₂/MeOH/NH₄OH 95/5/0.5): Rf=0.12.

Example 278N-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine278A

To a solution of2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)-methyl]phenylsulfanyl}ethylamine(130 mg) in acetonitrile (2 mL) is added N,N′-bis-Boc-guanylpyrazole(112 mg) and diisopropylethylamine (0.066 mL) at room temperature. Themixture is heated at 50° C. for 5 h. Water is added and the aqueousphase is extracted by ethyl acetate. The organic phase is dried overmagnesium sulfate and concentrated. The residue is purified bychromatography (gradient dichloromethane/methanol/ammonia from 95/5/0 to90/10/0 then 90/10/1).

The residue is then dissolved in 6N aqueous hydrochloric acid (1.5 mL)and the solution is stirred overnight at room temperature. The reactionmixture is neutralized to pH7 by adding dropwise 30% sodium hydroxidesolution. The solvent is removed under reduced pressure and the residueis triturated with a (dichloromethane/methanol)(95/5) and filtered. Thefiltrate is evaporated under reduced pressure to giveN-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidineas the dihydrochloride salt.

m/z: [M+H]⁺=439.0

278B

2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-ethylaminecan be prepared as described in example 249.

Following compounds are prepared analogously:

Example Product 3944-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}piperidine-1-carboxamidine hydrochloride ¹H NMR (DMSO-d⁶): 7.48-7.38 (m, 2H), 7.34(s, 1H), 7.32-7.20 (m, 2H), 7.17-7.00 (m, 3H), 5.78 (s, 1H), 3.98 (sl,1H), 3.92 (sl, 1H), 2.88-2.50 (m, 4H), 2.07 (s, 3H), 2.00-1.75 (m, 4H),1.75-1.45 (m, 6H)

Example 2934-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}butylamine,dichlorhydrate 293A

To a solution of4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)-methyl]phenyl}but-3-ynylamine(50 mg) in methanol (2.5 mL) is added platinum oxide (8 mg). The flaskis purged with argon then put under one atmosphere of hydrogen. Thereaction mixture is stirred overnight at room temperature then filteredon celite, cake washed with methanol. The solvent is removed underreduced pressure to give4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}butylamine.

m/z: [M+H]⁺=393.1; [M+Na]⁺=415.2

293B

4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynylaminecan be prepared according to general method in example 194.

Following compounds are prepared analogously:

Example Product 2384-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}butan-1-ol¹H NMR: 7.98 (d, 2H), 7.87 (d, 1H), 7.50-7.25 (m, 6H), 7.13 (d, 1H),5.88 (s, 1H), 3.81-3.70 (m, 1H), 7.70-7.60 (m, 2H), 3.98-2.80 (m, 2H),2.65 (t, 2H), 2.43 (s, 3H), 2.22-1.50 (m, 10H), 1.34 (t, 1H) 3962-{(1-methylpiperidin-4-yloxy)[3-(2-piperidin-4-yl-ethyl)phenyl]methyl}-1H-benzimidazole ¹H NMR: 7.65-7.50 (m, 2H), 7.35-7.15 (m, 5H), 7.03 (d,1H), 5.85 (s, 1H), 3.75 (t, 2H), 3.65-3.50 (m, 1H), 3.45-3.30 (m, 2H),2.90-2.65 (m, 4H), 2.58-2.45 (m, 2H), 2.28 (s, 3H), 2.28-2.10 (m, 2H),2.10-1.65 (m, 5H), 1.65-1.35 (m, 4H)

Following compounds are prepared according to the general methods:

General Example Product methods m/z 98{3′-[benzothiazol-2-yl(1-methylpiperidin-4- 53 [M + H]+ = 454.2yloxy)methyl]biphenyl-3-yl}acetonitrile, oxalate 1392-[(3′-fluorobiphenyl-3-yl)(1-methylpiperidin-4- 53 [M + H]⁺ = 433.1yloxy)methyl]benzothiazole 140 2-[(1-methylpiperidin-4-yloxy)(4′- 53[M + H]⁺ = 483.2 trifluoromethylbiphenyl-3-yl)methyl]benzothiazole 1412-[(1-methylpiperidin-4-yloxy)(2′,3′,4′-trifluorobiphenyl- 53 [M + H]⁺ =468.6 3-yl)methyl]benzothiazole 143{3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)- 53 [M + H]⁺ = 530.2methyl]biphenyl-4-yl}carbamic acid tert-butyl ester 320N-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 278A, [M + H]⁺ =421.0 yloxy)methyl]phenyl}propyl)guanidine, trihydrochloride 249, 149A321 N-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 278A, [M + H]⁺= 421.2 yloxy)methyl]phenyl}propyl)guanidine, trihydrochloride 249, 149A[M + Na]⁺ = 443.2 344 6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-293, 194 [M + H]⁺ = 421.2 yloxy)methyl]phenyl}hexylamine 346N-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 278A, [M + H]⁺ =459.2 yloxy)methyl]phenyl}hex-5-ynyl)guanidine, 249, 149A hydrochloride355 N-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 278A, [M + H]⁺= 463.2 yloxy)methyl]phenyl}hexyl)guanidine, trihydrochloride 249, 149A[M + Na]⁺ = 485.3 358N-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 278A, [M + H]⁺ =445.2 yloxy)methyl]phenyl}pent-4-ynyl)guanidine, 249, 149A [M + Na]⁺ =467.3 hydrochloride 372 N-(4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-278A, [M + H]⁺ = 448.1 yloxy)methyl]phenyl}but-3-ynyl)guanidine, 249,149A dihydrochloride 393N-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 278A, [M + H]⁺ =431.1 yloxy)methyl]phenyl}but-3-ynyl)guanidine, 249, 149A hydrochloride397 N-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 278A, [M + H]⁺= 449.2 yloxy)methyl]phenyl}pentyl)guanidine, hydrochloride 249, 149A[M + Na]⁺ = 471.2 418N-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 278A, [M + H]⁺ =417.1 yloxy)methyl]phenyl}prop-2-ynyl)guanidine, 249, 149A hydrochloride426 3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 278A, [M + H]⁺ =443.1 yloxy)methyl]phenylethynyl}azetidine-1-carboxamidine 249, 149A[M + Na]⁺ = 465.4

Example 298(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-ethyl)urea298A

To a solution of2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)-methyl]phenylsulfanyl}ethylamine

(50 mg) in ethanol (0.5 mL) in a screw-cap tube is added potassiumcyanate (15 mg). The reaction mixture is heated at 80° C. for 24 hours.The mixture is diluted water, basified to pH 9 by adding of an aqueoussaturated solution of sodium carbonate and extracted with ethyl acetate.The pooled organic extracts are dried over magnesium sulfate andconcentrated under reduced pressure. The residue is purified bychromatography (gradient dichloromethane/methanol/ammonia from 95/5/0.5to 90/10/1) to afford(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)ureamelting at 136° C.

298B

2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-ethylaminecan be prepared according to the method described in example 249.

Following compounds are prepared analogously:

Example Product 299 (2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl-sulfanyl}ethyl)(4,5-dihydrothiazol- 2-yl)amine ¹HNMR (DMSO-d⁶): 12.37 (sl, 1H), 7.53-7.38 (m, 3H), 7.27-6.95 (m, 5H),5.80 (s, 1H), 3.80 (t, 2H), 3.45-3.00 (m, 7H), 2.65-2.50 (m, 2H), 2.07(s, 3H), 2.00-1.75 (m, 4H), 1.65-1.45 (m, 2H) 317(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-phenylsulfanyl}ethyl)(4,5-dihydro-1H- imidazol-2-yl)amine¹H NMR (DMSO-d⁶): 12.90 (sl, 1H), 10.80 and 10.40 (sl, 1H), 8.58-8.42(m, 1H), 7.53-7.38 (m, 3H), 7.27-6.95 (m, 5H), 5.93 (s, 1H), 3.80 (t,2H), 3.45-3.00 (m, 7H), 2.65-2.50 (m, 2H), 2.07 (s, 3H), 2.00-1.75 (m,4H), 1.65-1.45 (m, 2H) 3471-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)-3-isopropylthiourea ¹H NMR: 10.43(sl, 1H), 7.72-7.50 (m, 3H), 7.35-7.20 (m, 5H), 6.45-6.15 (m, 2H), 5.83(s, 1H), 4.05-3.50 (m, 4H), 3.45-3.05 (m, 2H), 3.00-2.75 (m, 2H), 2.39(s, 3H), 2.20-1.75 (m, 4H), 1.22 (m, 1H), 1.02 (d, 3H), 0.91 (d, 3H)

Example 3055-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}pentylamine,oxalate 305A

2-(5-{3-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-pentyl)isoindole-1,3-dione(200 mg) is dissolved in ethanol (1 mL) and hydrazine hydrate (0.1 mL)is added. The reaction mixture is stirred at room temperature overnight.The mixture is evaporated to dryness and the residue is purified bychromatography (gradient dichloromethane/methanol/ammonia from 98/2/0.2to 90/10/1). The residue is added to oxalic acid (1 equivalent) inacetone (0.5 ml), and the precipitate is filtered and dry to give5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}pentylamine,oxalate melting at 201° C.

305B2-(5-{3-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-pentyl)isoindole-1,3-dione

A screw-cap tube is charged with2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole (200mg), palladium bis(dibenzylideneacetone) (14 mg), Xantphos (14 mg),thioacetic acid 5-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pentyl ester(209 mg), diisopropylethylamine (170 μL), potassium phosphate (105 mg),water (0.05 mL) and 1,4-dioxane (2 mL). The tube is evacuated, filledwith argon and sealed. After stirring at 120° C. for 48 h, solvents areremoved under reduced pressure. The residual solution is basified byadding a solution of saturated sodium carbonate to pH 10 and the aqueousphase is extracted with ethyl acetate. The pooled organic extracts aredried over magnesium sulfate and concentrated under reduced pressure.The residue is purified by chromatography (gradientdichloromethane/methanol/ammonia from 100/0/0 to 95/5/0.5) to give2-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylpentyl)isoindole-1,3-dionethat is used without further purification.

Example 307N-tert-butoxycarbonyl-N′-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynyl)guanidine307A

To a solution of4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)-methyl]phenyl}but-3-ynylamine(290 mg) in acetonitrile (4.5 mL) is added N,N′-bis-Boc-guanylpyrazole(255 mg) and diisopropylethylamine (0.15 mL) at room temperature. Themixture is heated at 50° C. overnight. Water is added and the aqueousphase is extracted by ethyl acetate. The organic phase is dried overmagnesium sulfate and concentrated. The residue is purified bychromatography (gradient dichloromethane/methanol/ammonia from 95/5/0 to90/10/0 then 90/10/1).

A part of the residue (100 mg) is then dissolved in 1,2-dichloroethane(2 mL); phenol (149 mg) and chlorotrimethylsilane (0.2 mL) are added andthe solution is heated at 50° C. for 20 h. Solvent and volatiles areremoved under reduced pressure. The residue is purified bychromatography (gradient dichloromethane/methanol/ammonia from 95/5/0 to90/10/0 then 90/10/1) to giveN-tert-butoxycarbonyl-N′-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynyl)guanidine.

¹H NMR: 7.54 (sl, 2H), 7.32 (s, 1H), 7.27-7.19 (m, 6H), 5.67 (s, 1H),3.70-3.52 (m, 1H), 3.52-3.32 (m, 2H), 2.85-2.65 (m, 2H), 2.61 (t, 2H),2.24 (s, 3H), 2.20-2.02 (m, 2H), 1.92-1.50 (m, 4H), 1.49 (t, 9H)

307B

4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynylaminecan be prepared as described in example 194A.

Example 3152-{(1-methylpiperidin-4-yloxy)[3-(4-[1,2,3]triazol-2-yl-butoxy)phenyl]methyl}-benzothiazole,oxalate 315A

60% in oil sodium hydride (20 mg) is washed with pentane and dilutedwith anhydrous N,N-dimethylformamide (5 mL). 1H-1,2,3-triazole is thenadded. After stirring at room temperature for 15 min, the mixture istreated with2[[3-(4-chloro-butoxy)phenyl]-(1-methyl-piperidin-4-yloxy)methyl]benzothiazole(223 mg) and warmed at 60° C. for one night. The mixture is then pouredinto water and extracted with diethylether. The pooled organic extractsare dried over magnesium sulfate and concentrated under reducedpressure. Purification of the residue by chromatography (gradientdichloromethane/methanol/ammonia from 98/2/0.5 to 90/10/0.5) affords thepure base that is then converted into its oxalate salt in acetone togive2-{(1-methylpiperidin-4-yloxy)[3-(4-[1,2,3]triazol-2-yl-butoxy)phenyl]methyl}benzothiazole,oxalate. TLC of the base (eluent: CH₂Cl₂/MeOH/NH₄OH 90/10/0.5): Rf=0.30.

315B

2[[3-(4-Chlorobutoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazolecan be prepared according to the described general methods 272A and 1B.

Example 3162-{(1-methylpiperidin-4-yloxy)[3-(4-[1,2,4]triazol-1-yl-butoxy)phenyl]methyl}-benzothiazole,oxalate

2-{(1-methylpiperidin-4-yloxy)[3-(4-[1,2,4]triazol-1-yl-butoxy)phenyl]methyl}-benzothiazole,oxalate can be prepared according general procedure 315A. TLC of thebase (eluent: CH₂Cl₂/MeOH/NH₄OH 90/10/0.5): Rf=0.22.

Example 318N-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-ethyl)-N′-cyanoguanidine318A

To a solution of2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)-methyl]phenylsulfanyl}ethylamine(50 mg) in isopropanol (1 mL) in a screw-cap tube is addeddiphenylcyanocarbonimidate (30 mg). The reaction mixture is stirred atroom temperature overnight. Solvent is removed under reduced pressureand the residual solid is dried. This solid is dissolved in ethanol (2mL) saturated with ammonia gas in a screw-cap tube. The tube is sealedand the reaction mixture is heated to 80° C. for 2 hours. The solventand volatiles are removed under reduced pressure. The residue ispurified by chromatography (gradient dichloromethane/methanol/ammoniafrom 98/2/0.2 to 90/10/1) to affordN-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)-N′-cyanoguanidinemelting at 65° C.

318B

2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-ethylaminecan be prepared according to the method described in example 249.

Example 3382-{(1-methylpiperidin-4-yloxy)[3-(1,2,3,6-tetrahydro-pyridin-4-yl)phenyl]methyl}-1H-benzimidazole338A

To a solution of4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (407 mg) in dichloromethane (2 mL) is addedtrifluoroacetic acid (1 mL). After 2 hours at room temperature,volatiles are removed under reduced pressure. The mixture is dilutedwith water, basified to pH 10 by adding of an aqueous saturated solutionof sodium carbonate and extracted with ethyl acetate. The pooled organicextracts are dried over magnesium sulfate and concentrated under reducedpressure. The residue is purified by chromatography (gradientdichloromethane/methanol/ammonia from 100/0/0 to 85/15/1.5) to afford2-{(1-methylpiperidin-4-yloxy)[3-(1,2,3,6-tetrahydro-pyridin-4-yl)phenyl]methyl}-1H-benzimidazole.

¹H NMR: 10.0 (sl, 1H), 7.60 (s, 1H), 7.70-7.45 (m, 2H), 7.40-7.20 (m,5H), 6.06 (s, 1H), 5.87 (s, 1H), 3.50 (t, 2H), 3.65-3.45 (m, 1H), 3.08(d, 2H), 2.80-2.75 (m, 2H), 2.60-2.22 (m, 3H), 2.26 (s, 3H), 2.20-1.65(m, 6H)

338A

4-{3-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester can be prepared according to the proceduredescribed in example 53.

Example 3594-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butylamine,oxalate 359A

(4-{3-[Benzothiazol-2-yl-(1-methyl-piperidin-4-yloxy)-methyl]-phenylsulfanyl}-butyl)-carbamicacid tert-butyl ester (140 mg) is dissolved in dichloromethane (1 mL)and trifluoroacetic acid (0.4 mL) is added. The reaction mixture isstirred at room temperature for 1 hour. The mixture is evaporated todryness. The residue is basified by adding a solution of saturatedsodium carbonate to pH 10 and the aqueous phase is extracted withdichloromethane. The pooled organic extracts are dried over magnesiumsulfate and concentrated under reduced pressure. The residue is purifiedby chromatography (gradient dichloromethane/methanol/ammonia from100/0/0 to 90/10/1). The residue is added to oxalic acid (1 equivalent)in acetone (0.5 ml), and the precipitate is filtered and dry to give4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butylamine,oxalate melting at 108° C.

359B(4-{3-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butyl)-carbamicacid tert-butyl ester

A screw-cap tube is charged with2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole (200mg), palladium bis(dibenzylideneacetone) (14 mg), Xantphos (14 mg),thioacetic acid S-(4-tert-butoxycarbonylaminobutyl) ester (180 mg),potassium phosphate (200 mg), water (0.01 mL) and 1,4-dioxane (2 mL).The tube is evacuated, filled with argon and sealed. After stirring at120° C. for 48 h, solvents are removed under reduced pressure. Theresidue is basified by adding a solution of saturated sodium carbonateto pH 10 and the aqueous phase is extracted with ethyl acetate. Thepooled organic extracts are dried over magnesium sulfate andconcentrated under reduced pressure. The residue is purified bychromatography (gradient dichloromethane/methanol/ammonia from 100/0/0to 95/5/0.5) to give(4-{3-[(1H-benzimidazol-2-yl)-(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butyl)carbamicacid tert-butyl ester that is used without further purification.

Example 3762-[(1-methylpiperidin-4-yloxy)(3-piperidin-4-ylethynyl-phenyl)methyl]-1H-benzimidazole376A

To a solution of4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)-methyl]phenylethynyl}piperidine-1-carboxylicacid tert-butyl ester (160 mg) in 1,2-dichloroethane (10 mL) are addedphenol (940 mg) and chlorotrimethylsilane (1.26 mL). The reactionmixture is heated to 100° C. for 30 minutes. Volatiles are removed underreduced pressure. The residue is purified by chromatography (gradientdichloromethane/methanol/ammonia from 100/0/0 to 85/15/1.5) to afford2-[(1-methylpiperidin-4-yloxy)(3-piperidin-4-ylethynyl-phenyl)methyl]-1H-benzimidazole.

¹H NMR: 9.80 (sl, 1H), 7.50 (s, 1H), 7.80-7.50 (m, 2H), 7.45-7.20 (m,5H), 5.84 (s, 1H), 3.65-3.50 (m, 1H), 3.25-3.10 (m, 2H), 2.90-2.35 (m,7H), 2.25 (s, 3H), 2.20-1.65 (m, 9H)

376B

4-{3-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylethynyl}-piperidine-1-carboxylicacid tert-butyl ester can be prepared according to the proceduredescribed in example 189.

Example 3845-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-en-1-ol384A

To a solution of Acetic acid5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-enylester (150 mg) in a mixture of water (1 mL), 1,4-dioxane (1 mL) andmethanol (1 mL) is added 1N sodium hydroxide solution (0.6 mL). Thereaction mixture is stirred at room temperature for 2 hours. Afterneutralization to pH 7 with addition of 1N hydrochloric acid, thereaction mixture is extracted with dichloromethane. The pooled organicextracts are dried over magnesium sulfate and concentrated under reducedpressure. The residue is purified by chromatography (gradientdichloromethane/methanol/ammonia from 95/5/0.5 to 90/10/1) to afford5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-en-1-ol.

¹H NMR: 7.97 (d, 1H), 7.86 (dd, 1H), 7.53-7.24 (m, 6H), 6.32 (dd, 1H),6.27 (dd, 1H) 5.30 (s, 1H), 3.71 (t, 2H), 3.77-3.60 (m, 1H), 3.00-2.90(m, 2H), 2.80-2.68 (m, 2H), 2.30 (s, 3H), 2.37-2.15 (m, 4H), 2.20-1.55(m, 5H)

384B

Acetic acid5-{3-[benzothiazol-2-yl-(1-methyl-piperidin-4-yloxy)-methyl]-phenyl}-pent-4-enylester can be prepared according to the method described in example 53.

Following examples can be prepared analogously:

Example Product General methods 1562-[[3-(2,5-difluorobenzyloxy)phenyl](1-methylpiperidin-4- 1A, 168Byloxy)methyl]benzothiazole, oxalate ¹H NMR of the base (CDCl₃): 7.96 (d,1H), 7.85 (d, 1H), 6.90-7.50 (m, 9H), 5.86 (s, 1H), 5.10 (s, 2H), 3.83(m, 1H), 2.97 (m, 2H), 2.83 (m, 2H), 2.61 (s, 3H), 2.20 (m, 2H), 1.93(m, 2H). 263 2-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 259A, 150yloxy)methyl]phenylsulfanyl}acetamide ¹H NMR (DMSO-d⁶): 8.03 (s, 1H),7.86 (d, 1H), 7.61 (sl, 1H), 7.48-7.18 (m, 6H), 7.11 (sl, 1H), 5.95 (s,1H), 3.57 (s, 2H), 3.57-3.45 (m, 1H), 2.62-2.40 (m, 2H), 2.07 (s, 3H),2.07-1.72 (m, 4H), 1.70-1.35 (m, 2H) 309N-tert-butoxycarbonyl-N′-(4-{3-[(1H-benzimidazol-2-yl)(1- 307A, 194Amethylpiperidin-4-yloxy)methyl]phenyl}butyl)guanidine ¹H NMR: 7.65-7.55(m, 2H), 7.38 (s, 1H), 7.30-7.15 (m, 4H), 7.01 (d, 1H), 5.79 (s, 1H),3.70-3.55 (m, 1H), 3.18-2.95 (m, 4H), 2.55-2.30 (m, 4H), 2.44 (s, 3H),2.15-1.95 (m, 2H), 1.95-1.70 (m, 2H), 1.65-1.50 (m, 4H), 1.49 (s, 9H)313 N-tert-butoxycarbonyl-N′-(3-{3-[(1H-benzimidazol-2-yl)(1- 307A, 194Amethylpiperidin-4-yloxy)methyl]phenyl}propyl)amine ¹H NMR: 7.68-7.58 (m,2H), 7.52 (s, 1H), 7.30-7.15 (m, 4H), 7.01 (d, 1H), 5.79 (s, 1H),3.85-3.70 (m, 1H), 3.45-3.18 (m, 4H), 2.78-2.50 (m, 4H), 2.62 (s, 3H),2.20-1.60 (m, 6H), 1.46 (s, 9H) 335N-tert-butoxycarbonyl-N′-(-{3-[(1H-benzimidazol-2-yl)(1- 307A, 194Amethylpiperidin-4-yloxy)methyl]phenyl}pentyl)guanidine, hydrochloride ¹HNMR: 8.95 (sl, 1H), 7.68-7.58 (m, 2H), 7.41 (s, 1H), 7.32-7.15 (m, 4H),7.01 (d, 1H), 5.78 (s, 1H), 3.92-3.82 (m, 1H), 3.70-3.25 (m, 4H),3.20-2.70 (m, 4H), 2.81 (s, 3H), 2.52 (t, 2H), 2.30-1.85 (m, 4H),1.70-1.50 (m, 2H), 1.49 (s, 9H), 1.35-1.20 (m, 2H) 336N-tert-butoxycarbonyl-N′-(3-{3-[(1H-benzimidazol-2-yl)(1- 307A, 194Amethylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)guanidine ¹H NMR:7.68-7.58 (m, 2H), 7.41 (s, 1H), 7.32-7.15 (m, 4H), 7.01 (d, 1H), 5.78(s, 1H), 4.27 (s, 2H), 3.92-3.82 (m, 1H), 3.10-2.80 (m, 2H), 2.37 (s,3H), 2.65-2.30 (m, 2H), 2.15-1.90 (m, 2H), 1.90-1.65 (m, 2H), 1.46 (s,9H) 345 N-tert-butoxycarbonyl-N′-(6-{3-[(1H-benzimidazol-2-yl)(1- 307A,194A methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)guanidine ¹H NMR(DMSO-d⁶): 10.91 (sl, 1H), 8.71 (sl, 1H), 7.65-7.48 (m, 2H), 7.48-7.15(m, 6H), 6.00 (s, 1H), 3.80 (s, 1H), 3.00-2.82 (m, 2H), 2.75 (m, 2H),3.63 (m, 2H), 2.43 (s, 3H), 2.15-2.05 (m, 2H), 1.98-1.75 (m, 2H),1.75-1.55 (m, 6H), 1.44 (s, 9H) 3514-(3-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 370A, 272Ayloxy)methyl]phenoxy}propyl)piperazine-1-carboxylic acid tert- and 1Bbutyl ester, oxalate ¹H NMR of the base (CDCl₃): 7.96 (d, 1H), 7.82 (d,1H), 7.50-7.20 (m, 3H), 7.07 (m, 2H), 6.79 (d, 1H), 5.86 (s, 1H), 3.97(t, 2H), 3.60 (m, 1H), 3.40 (m, 4H), 2.67 (m, 2H), 2.48 (t, 2H), 2.36(m, 4H), 2.23 (s, 3H), 2.13 (m, 2H), 2.00-1.70 (m, 6H), 1.44 (s, 9H) 3534-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 376A, 189yloxy)methyl]phenyl}-3,6-dihydro-2H-pyridine-1-carboxamidine,hydrochloride ¹H NMR (DMSO-d⁶): 10.7 and 10.45 (sl, 1H), 7.68-7.50 (m,1H), 7.50-7.35 (m, 2H), 7.28-7.10 (m, 5H), 6.20 (s, 1H), 5.95 (d, 1H),4.06 (s, 2H), 3.79 (s, 1H), 3.58 (t, 2H), 3.05-2.80 (m, 2H), 2.74 (s,2H), 2.65-2.50 (m, 2H), 2.48 (s, 3H), 2.25-2.05 (m, 2H), 2.00-1.75 (m,2H) 357 N-tert-butoxycarbonyl-N′-(5-{3-[(1H-benzimidazol-2-yl)(1- 307A,194A methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)guanidine ¹H NMR(DMSO-d⁶): 12.55 (sl, 1H), 8.67 (sl, 1H), 7.68-7.40 (m, 2H), 7.40-7.25(m, 3H), 7.20-7.05 (m, 3H), 5.86 (s, 1H), 3.78-3.50 (m, 1H), 3.10-2.80(m, 2H), 2.75-2.50 (m, 4H), 2.46 (s, 3H), 2.20-1.65 (m, 8H), 1.42 (s,9H) 383 2-{(1-methylpiperidin-4-yloxy)[3-(pyrrolidin-3- 258yloxy)phenyl]methyl}benzothiazole, dioxalate ¹H NMR of the base (CDCl₃):7.98 (d, 1H), 7.87 (d, 1H), 7.46-7.20 (m, 3H), 7.09 (m, 2H), 6.80 (d,1H), 5.89 (s, 1H), 4.83 (m, 1H), 3.63 (m, 2H), 3.17 (m, 1H), 3.00-2.85(m, 2H), 2.68 (m, 2H), 2.28 (s, 3H), 2.20-1.70 (m, 8H) 3905-{3-[(benzothiazol-2-yl)(1-methylpiperidin-4- 384A, 53yloxy)methyl]phenyl}pent-4-en-1-ol ¹H NMR: 7.97 (d, 1H), 7.86 (dd, 1H),7.54 (s, 1H), 7.50-7.25 (m, 4H), 7.19 (d, 1H), 6.43 (dd, 1H), 6.27 (dd,1H) 5.94 (s, 1H), 5.73 (dd, 1H), 3.77-3.60 (m, 3H), 2.87-2.70 (m, 2H),2.55-2.20 (m, 2H), 2.33 (s, 3H), 2.20-1.65 (m, 7H)

Example 3853-amino-4-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamino)-cyclobut-3-ene-1,2-dione385A

To a solution of2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)-methyl]phenylsulfanyl}ethylamine(150 mg) in diethylether (10 mL) is added L). The reaction mixture isstirred at □3,4-diethoxy-3-cyclobutene-1,2-dione (56 room temperaturefor 1 hour. The mixture is filtered, washed with diethylether and dried.The residue is dissolved in ethanol (2 mL) saturated with ammonia gas ina screw-capped tube. The tube is sealed and the reaction mixture isheated to 80° C. for 2 hours. The solvent and volatiles are removedunder reduced pressure. The residue is purified by chromatography(gradient dichloromethane/methanol/ammonia from 98/2/0.2 to 90/10/1) toafford3-amino-4-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamino)-cyclobut-3-ene-1,2-dionemelting at 161° C.

385B

2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-ethylaminecan be prepared according to the method described in example 249.

Example 386[[3-(6-aminohex-1-ynyl)phenyl](1H-benzimidazol-2-yl)methyl](1-methylpiperidin-4-yl)amine386A

A solution of2-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-ylamino)-methyl]phenyl}pent-4-ynyl)isoindole-1,3-dione(230 mg) and hydrazine hydrate (120 μL) in ethanol (3 mL) is stirred aroom temperature for one night. The mixture is then concentrated underreduced pressure and the residue purified by chromatography(dichloromethane/methanol/ammonia from 90/10/0.5) to afford[[3-(6-aminohex-1-ynyl)phenyl](1H-benzimidazol-2-yl)methyl](1-methylpiperidin-4-yl)aminemelting at 79° C.

386B

2-(5-{3-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-ylamino)methyl]phenyl}pent-4-ynyl)isoindole-1,3-dionecan be prepared according to general procedure 275 starting from[(1H-benzimidazol-2-yl)(3-iodo-phenyl)methyl](1-methylpiperidin-4-yl)amine.

Example 3982-[{3-[3-(3H-imidazol-4-yl)propylsulfanyl]phenyl}(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole398A

To a solution of2-((1-methylpiperidin-4-yloxy){3-[3-(1-trityl-1H-imidazol-4-yl)propylsulfanyl]phenyl}methyl)-1H-benzimidazole(200 mg) in 1,2-dichloroethane (7 mL) are added phenol (270 mg) andchlorotrimethylsilane (0.37 mL). The reaction mixture is heated atreflux overnight. Volatiles are removed under reduced pressure and theresidue is purified by chromatography (gradientdichloromethane/methanol/ammonia from 98/2/0.2 to 90/10/1) to give2-[{3-[3-(3H-imidazol-4-yl)propylsulfanyl]phenyl}(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole.

¹H NMR: 7.72-7.40 (m, 4H), 7.25-7.15 (m, 5H), 6.82 (s, 1H), 5.84 (s,1H), 3.60-3.45 (m, 1H), 3.00-2.65 (m, 6H), 2.25 (s, 3H), 2.15-1.60 (m,8H)

398B

2-((1-Methylpiperidin-4-yloxy){3-[3-(1-trityl-1H-imidazol-4-yl)propylsulfanyl]phenyl}-methyl)-1H-benzimidazolecan be prepared according to the method described in example 359A.

Example 401N-acetyl-N′-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine401A

To a solution ofN-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)-methyl]phenylsulfanyl}ethyl)guanidine.dihydrochloride(100 mg) in dry acetonitrile (1 mL) is added acetic anhydride (64 mg) et4-dimethylaminopyridine (51 mg). After 24 hours at room temperature,solvent and volatiles are removed under reduced pressure. The residue ispurified by chromatography (toluene/acetone/triethylamine 50/50/1 thengradient dichloromethane/methanol/ammonia from 95/5/0.5 to 90/10/1) togiveN-acetyl-N′-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine.

¹H NMR (DMSO-d⁶): 12.40 (sl, 1H), 7.55-7.40 (m, 1H), 7.40-7.20 (m, 3H),7.20-7.05 (m, 4H), 5.81 (s, 1H), 3.50-3.05 (m, 3H), 2.65-2.55 (m, 2H),2.46 (s, 3H), 2.07 (s, 3H), 2.02-1.72 (m, 4H), 1.68-1.45 (m, 4H).

401B

N-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-ethyl)guanidinecan be obtained according to the method described in example 278.

Example 4031-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}azetidin-3-ol,oxalate

A screw-capped tube is charged with2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole(example 41, 150 mg), copper(I) iodide (15 mg), deanol (1 mL), potassiumcarbonate (306 mg), azetidin-3-ol, hydrochloride (88 mg). The tube isevacuated, filled with argon and sealed. After stirring at 60° C. for100 h, the mixture is diluted with dichloromethane, water and ammonia.After decantation, the aqueous phase is extracted with dichloromethane.The pooled organic extracts are dried over magnesium sulfate andconcentrated under reduced pressure. The residue is purified bychromatography (gradient dichloromethane/methanol/ammonia from 95/5/0.5to 90/10/0.5). The base is converted into its oxalate salt in acetone togive1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}azetidin-3-ol,oxalate melting at 117° C.

Example 4111-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}piperidin-4-ol,oxalate

A solution of acetic acid1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}piperidin-4-ylester (example 413, 100 mg) and aqueous 1N sodium hydroxide in methanol(1 mL) is stirred at room temperature for 30 min. The mixture is dilutedwater and extracted with dichloromethane. The pooled organic extractsare dried over magnesium sulfate and concentrated under reducedpressure. The residue is purified by chromatography (gradientdichloromethane/methanol/ammonia from 95/5/0.5 to 90/10/0.5). The baseis converted into its oxalate salt in acetone to give1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}piperidin-4-ol,oxalate melting at 110° C.

Example 4122-[{3-[2-(1H-imidazol-4-yl)ethyl]phenyl}(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole412A

To a solution of2-{(1-methylpiperidin-4-yloxy)[3-(1-trityl-1H-imidazol-4-ylethynyl)phenyl]methyl}-1H-benzimidazole(260 mg) in 1,2-dichloroethane (7 mL) are added phenol (374 mg) andchlorotrimethylsilane (0.51 mL). The reaction mixture is heated atreflux overnight. Volatiles are removed under reduced pressure and theresidue is purified by chromatography (gradient dichloromethane/methanolfrom 95/5 to 90/10 then dichloromethane/methanol/ammonia 90/10/1).

The residue is then dissolved in methanol (3 mL) and palladium oncharcoal (8 mg). is added. The flask is purged with argon then put underone atmosphere of hydrogen. The reaction mixture is stirred overnight atroom temperature then filtered on celite, cake washed with methanol. Thesolvent is removed under reduced pressure to give2-[{3-[2-(1H-imidazol-4-yl)ethyl]phenyl}(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole.

¹H NMR (methanol-d⁴): 7.65-7.55 (m, 3H), 7.40-7.15 (m, 6H), 6.70 (s,1H), 5.85 (s, 1H), 3.80-3.70 (m, 1H), 3.28-3.10 (m, 2H), 3.05-2.75 (m,6H), 2.64 (s, 3H), 2.15-1.85 (m, 4H).

412B

2-{(1-Methylpiperidin-4-yloxy)[3-(1-trityl-1H-imidazol-4-ylethynyl)phenyl]methyl}-1H-benzimidazolecan be prepared according to the method described in example 189.

Example 4162-{(1-methylpiperidin-4-yloxy)[3-(5-[1,2,3]triazol-2-yl-pent-1-ynyl)phenyl]methyl}-1H-benzimidazole416A

To a solution of 1,2,3-triazole (66 mg) in DMF (0.6 mL) is added sodiumhydride (25 mg). After gas evolution ceased,2[[3-(5-chloropent-1-ynyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole(50 mg) and a catalytic quantity of n-tetrabutylammonium iodide areadded. After stirring overnight at room temperature, the solvent isremoved under reduced pressure to dryness. The residue is purified bychromatography (dichloromethane/methanol/ammonia 90/10/1) to afford2-{(1-methylpiperidin-4-yloxy)[3-(5-[1,2,3]triazol-2-yl-pent-1-ynyl)phenyl]methyl}-1H-benzimidazole.

¹H NMR: 9.43 (sl, 1H), 7.83-7.68 (m, 1H), 7.60 (s, 2H), 7.52 (s, 1H),7.50-7.20 (m, 6H), 5.84 (s, 1H), 4.61 (t, 2H), 3.68-3.50 (m, 1H),2.88-2.70 (m, 2H), 2.46 (t, 2H), 2.30 (s, 3H), 2.38-2.10 (m, 4H),2.10-1.65 (m, 6H).

416B

2[[3-(5-Chloropent-1-ynyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazolecan be obtained according to the synthetic method described in example189.

Following compounds are prepared analogously:

Example Product 4172-{(1-methylpiperidin-4-yloxy)[3-(5-[1,2,3]triazol-1-ylpent-1-ynyl)phenyl]methyl}-1H-benzimidazole ¹H NMR: 9.77 (sl, 1H), 7.83-7.68(m, 1H), 7.70 (s, 1H), 7.61 (s, 1H), 7.52 (s, 1H), 7.50-7.35 (m, 2H)7.35-7.20 (m, 4H), 5.84 (s, 1H), 4.58 (t, 2H), 3.70-3.55 (m, 1H),2.90-2.75 (m, 2H), 2.47 (t, 2H), 2.32 (s, 3H), 2.40-2.15 (m, 4H),2.15-1.70 (m, 4H) 4092-[[3-(5-imidazol-1-ylpent-1-ynyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole ¹H NMR: 10.90 (sl, 1H), 7.85-7.68 (m,1H), 7.69 (s, 1H), 7.60 (s, 1H), 7.37 (dt, 1H), 7.40-7.20 (m, 5H), 7.11(s, 1H), 7.00 (s, 1H), 5.84 (s, 1H), 4.17 (t, 2H), 3.68-3.50 (m, 1H),2.88-2.70 (m, 2H), 2.48 (t, 2H), 2.30 (s, 3H), 2.29-1.90 (m, 4H),1.90-1.50 (m, 4H)

Example 4215-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-enylamine421A

To a solution of5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)-methyl]phenyl}pent-4-ynylamine(200 mg) in N,N-dimethylformamide (1.8 mL) are added water (0.05 mL),potassium hydroxide (42 mg) and palladium(II) acetate. The tube isevacuated, filled with argon and sealed. After stirring at 120° C. for24 h, the mixture is filtered on celite, and the solvent removed underreduced pressure.diluted with water and the aqueous phase is extractedwith ethyl acetate. The pooled organic extracts are washed with water,dried over magnesium sulfate and concentrated under reduced pressure.The residue is purified by chromatography (gradientdichloromethane/methanol/ammonia from 90/10/0 to 90/10/1) to give5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-enylamine.

¹H NMR: 7.75-7.58 (m, 2H), 7.42-7.10 (m, 6H), 6.45 (d, 1H), 5.90 (s,1H), 5.72 (dt, 1H), 3.68-3.50 (m, 1H), 2.95-2.85 (m, 2H), 2.85-2.65 (m,2H), 2.50-2.35 (m, 2H), 2.25 (s, 3H), 2.25-1.65 (m, 8H),

421B

5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylaminecan be synthesized according to the procedure described in example 194.

Example 4231-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ylamine,dioxalate 423A

A solution of crude(1-{3-[benzothiazol-2-yl-(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)carbamicacid tert-butyl ester (289 mg) in dichloromethane (3 mL) andtrifluoroacetic acid (2.5 mL) is stirred at room temperature for onenight. The mixture is concentrated under reduced pressure, diluted withethyl acetate, washed with aqueous 1N sodium hydroxide, dried overmagnesium sulfate and concentrated under reduced pressure. The residueis purified by chromatography (gradient dichloromethane/methanol/ammoniafrom 95/5/0.5 to 80/20/0.5). The base is converted into its dioxalatesalt in acetone to give1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ylamine,dioxalate melting at 145° C.

423B

A screw-capped tube is charged with2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole(example 41, 200 mg), copper(I) iodide (7 mg), 2-isobutyrylcyclohexanone(25 mg), cesium carbonate (280 mg), 3-(Boc-amino)pyrrolidine (160 mg)and anhydrous N,N-dimethylformamide (1 mL). The tube is evacuated,filled with argon and sealed. After stirring at 55° C. for 4 days, themixture is diluted with ethyl acetate, water and ammonia. Afterdecantation, the aqueous phase is extracted with ethyl acetate. Thepooled organic extracts are dried over magnesium sulfate andconcentrated under reduced pressure. The residue is purified bychromatography (gradient dichloromethane/methanol/ammonia from 98/2/0.5to 95/5/0.5). to afford(1-{3-[benzothiazol-2-yl-(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)carbamicacid tert-butyl ester.

Example 432 432A2-(5-{3-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-pentyl)isoindole-1,3-dione

To a solution of5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}pentan-1-ol(35 mg) in tetrahydrofuran are added triphenylphosphine (31 mg) andphthalimide (18 mg). The reaction mixture is cooled to 0° C. and diethylazodicarboxylate (31 μL) is added. The reaction mixture is stirred at 0°C. for 30 minute. The mixture is evaporated to dryness and the residueis purified by chromatography (gradient dichloromethane/methanol/ammoniafrom 98/2/0.2 to 95/5/0.5) to give2-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}pentyl)isoindole-1,3-dione(example 305B).

432B

5-{3-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}pentan-1-olcan be prepared according to the method described in example 150.

Preparation of Starting Materials

1-Bromo-3-(2-fluoroethoxy)benzene is prepared from 3-bromophenol and2-fluoroethanol using standard Mitsunobu protocol.

1-Bromo-3-(3-fluoropropoxy)benzene is prepared from 3-bromophenol and3-fluoropropanol using standard Mitsunobu protocol.

2-[2-(3-Bromophenoxy)ethyl]-6,6-dimethylbicyclo[3.1.1]hept-2-ene isprepared from 3-bromophenol and2-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)ethanol using standardMitsunobu protocol.

Example 436N-(2-aminoethyl)-2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetamide

The compound is made from example 154 and ethylenediamine using methoddescribed in example 264. ¹H NMR: 7.68-7.48 (m, 2H), 7.35-6.95 (m, 8H),5.89 (s, 1H), 3.83-3.50 (m, 3H), 3.50-3.35 (m, 1H), 3.25-3.10 (m, 1H),2.82-2.62 (m, 3H), 2.59-2.45 (m, 1H), 2.26 (s, 3H), 2.24-1.95 (m, 3H),1.92-1.50 (m, 5H).

Example 437N-(2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine437A

To a solution of2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine(example 437B, 230 mg) in acetonitrile (15 mL) is added is addedN,N′-bis-Boc-guanylpyrazole (172 mg) and diisopropylethylamine (1equivalent) at room temperature. The mixture is stirred at roomtemperature for 3 h. The solvent and volatiles are removed under reducedpressure. The residue is purified by chromatography on silica gel(gradient dichloromethane/methanol from 100/0 to 95/5). The residue isthen dissolved in 5N aqueous hydrochloric acid (8 mL) and the solutionis stirred overnight at room temperature. The solvent and volatiles areremoved under reduced pressure and the residue is triturated withdiethyl ether and filtered to affordN-(2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine trihydrochloride as a white crystalline solid melting at 170°C.

437B2-{3-[(5-Fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine

To a solution of(2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)carbamicacid tert-butyl ester (example 437C, 386 mg) in chloroform (10 mL) areadded phenol (750 mg) and chlorotrimethylsilane (814 mg). The mixture isheated at reflux for 2 h. The solvent and volatiles are removed underreduced pressure. The residue is basified by adding a solution of 1Nsodium hydroxide. The aqueous phase is extracted by ethyl acetate. Theorganic phase is washed by water, then dried over magnesium sulfate andconcentrated. The residue is purified by chromatography on silica gel(gradient dichloromethane/methanol/ammonia from 100/0/0 to 90/10/1) togive2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine.

¹H NMR: 8.5-9 (sl, 1H), 7.53 (s, 1H), 7.32-7.20 (m, 5H), 7.08-6.98 (m,1H), 5.84 (s, 1H), 3.70-3.50 (m, 1H), 3.08-3.04 (m, 2H), 3.00-2.88 (m,2H), 2.87-2.70 (m, 2H), 2.33 (s, 3H), 2.30-1.60 (m, 8H).

437C(2-{3-[(5-Fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)carbamicacid tert-butyl ester

A screw-capped tube is charged with2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole(example 437D, 418 mg), palladium bis(dibenzylideneacetone) (30 mg),Xantphos (30 mg), (2-mercaptoethyl)carbamic acid tert-butyl ester (1equivalent), diisopropylethylamine (180 μL) and 1,4-dioxane (6 mL). Thetube is evacuated, filled with argon and sealed. After stirring at 120°C. overnight, the mixture is diluted with ethyl acetate and water andthe aqueous phase is extracted with ethyl acetate. The pooled organicextracts are dried over magnesium sulfate and concentrated under reducedpressure. The residue is purified by chromatography (gradientdichloromethane/methanol from 98/2 to 95/5) to afford(2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)carbamicacid tert-butyl ester. ¹H NMR: 11.07 (sl, 1H), 7.69-7.59 (m, 1H),7.39-7.36 (m, 1H), 7.30-7.15 (m, 2H), 7.04-6.91 (m, 2H), 5.83 (s, 1H),5.30 (sl, 1H), 4.20 (s, 2H), 3.65-3.40 (m, 3H), 3.30-3.05 (m, 2H),2.80-2.65 (m, 2H), 2.27 (s, 3H), 2.25-1.75 (m, 6H), 1.55 (s, 9H).

437 D2-[(3-Bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole

A mixture of (3-bromophenyl)(5-fluoro-1H-benzimidazol-2-yl)methanol(example 437E, 3.30 g) and 1-methylpiperidin-4-ol (2.37 g) inmethanesulfonic acid (10 mL) is heated overnight in a sealed tube at atemperature close to 140° C. The mixture is cooled back to roomtemperature, poured into water which is then made alkaline withconcentrated sodium hydroxide solution. The aqueous phase is extractedwith ethyl acetate. Pooled extracts are dried over magnesium sulfate,concentrated under reduced pressure. The residue is purified by columnchromatography over silica gel (gradientdichloromethane/methanol/ammonia from 100/0/0 to 90/10/1) to afford2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole.¹H NMR: 9.92 (sl, 1H), 7.60 (s, 1H), 7.55-6.85 (m, 6H), 5.80 (s, 1H),3.65-3.50 (m, 1H), 2.80-2.65 (m, 2H), 2.34 (s, 3H), 2.15-1.65 (m, 6H).

437E

(3-Bromophenyl)(5-fluoro-1H-benzimidazol-2-yl)methanol could besynthesized using the method described in example 449B.

Example 438 438A5-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamineoxalate

A solution of2-(5-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)isoindole-1,3-dione(example 438B, 170 mg) and hydrazine hydrate (200 μL) in ethanol (2.5mL) is stirred a room temperature overnight. Water is added and theaqueous phase is extracted by diethyl ether. The pooled organic extractsare dried over magnesium sulfate and concentrated under reducedpressure. The residue is purified by chromatography(dichloromethane/methanol/ammonia from 95/5/0.5 to 90/10/1)) to affordthe free base. One equivalent of oxalic acid in acetone is added to thefree base to afford5-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamineoxalate as a white crystalline solid melting at 150° C.

438B2-(5-{3-[(5-Fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)isoindole-1,3-dione

A screw-capped tube is charged with2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole(example 437D, 418 mg), PEPPSi-sono catalyst (19 mg), copper (I) iodide(38 mg), N-pentynylphthalimide (428 mg), diethylamine (880 μL) andN,N-dimethylformamide (1.5 mL). The tube is evacuated, filled with argonand sealed. The reaction mixture is stirred at 80° C. overnight. As thereaction is not completed, PEPPSi-sono catalyst (10 mg) andN-pentynylphthalimide (214 mg) are added, and the reaction mixture isheated at 80° C. for 24 h. The mixture is diluted with water and theaqueous phase is extracted with ethyl acetate. The pooled organicextracts are washed with water, dried over magnesium sulfate andconcentrated under reduced pressure. The residue is purified bychromatography (gradient dichloromethane/methanol from 98/2/to 90/10) togive2-(5-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)isoindole-1,3-dione.¹H NMR: 9.65 (sl, 1H), 7.84-7.65 (m, 4H), 7.54 (s, 1H), 7.48-6.95 (m,4H), 5.84 (s, 1H), 3.90 (t, 2H, J=6.9 Hz), 3.65-3.50 (m, 1H), 2.85-2.70(m, 2H), 2.52 (t, 2H, J=7.0 Hz), 2.32 (s, 3H), 2.28-1.50 (m, 8H).

General Example Product methods 4396-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1- 438methylpiperidin-4-yloxy)methyl]phenyl}hex- 5-ynylamine oxalate mp = 146°C. 440 4-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1- 432, 150methylpiperidin-4-yloxy)methyl]phenyl- sulfanyl}butylamine oxalate mp =160° C. 441 N-(3-{3-[(1H-benzimidazol-2-yl)(1- 278, 432,methylpiperidin-4-yloxy)methyl]phenyl- 150 sulfanyl}propyl)guanidine,dihydrochloride mp = 318° C.

Example 4431-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]-phenyl}pyrrolidin-3-one,oxalate

To a solution of oxalyl chloride (317 μL) in dichloromethane (8 mL) at−78° C. is added DMSO (517 μL). After 15 min, a solution of1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ol(example 406, 958 mg) in dichloromethane (18 mL) is slowly added at thesame temperature. After 45 min triethylamine (2 mL) is added and themixture allowed to warm to room temperature. After hydrolysis withaqueous saturated ammonium chloride, the organic phase is dried overmagnesium sulfate and concentrated under reduced pressure. Purificationof the residue by chromatography over silicagel(dichloromethane/methanol/ammonia 98/2/0.5) affords the pure basethat is then converted into its oxalate salt in acetone to give1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-one,oxalate melting at 105° C.

Example Product General methods 444N-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 278, 432,yloxy)methyl]phenylsulfanyl}butyl)guanidine, dihydrochloride 150 ¹H NMR:(methanol-d₄): 7.65-7.50 (m, 2H), 7.45 (s, 1H), 7.40-7.15 (m, 5H), 5.84(s, 1H), 3.70-3.55 (m, 1H), 3.10 (t, 2H, J = 6.6 Hz), 3.00-2.80 (m, 4H),2.5-2.30 (m, 5H), 2.08-1.75 (m, 4H), 1.70-1.55 (m, 4H). 4455-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 359Byloxy)methyl]phenylsulfanyl}pentan-1-ol ¹H NMR (methanol-d₄): 9.90 (sl,1H), 7.75-7.70 (m, 1H), 7.42-7.35 (m, 2H), 7.32-7.15 (m, 5H), 5.84 (s,1H), 3.70-3.48 (m, 3H), 2.89 (t, 2H, J = 6.6 Hz), 2.80-2.62 (m, 2H),2.24 (s, 3H), 2.15-1.42 (m, 12H). 446N-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 401yloxy)methyl]phenylsulfanyl}ethyl)-N-(2,2- dimethylpropionyl)guanidine¹H NMR: 12.34 (sl; 1H), 7.51 (d, 1H, J = 6.75 Hz), 7.48-7.40 (m, 2H),7.30-7.20 (m, 3H), 7.20-7.05 (m, 2H), 6.65 (sl, 1H), 5.81 (s, 1H),3.50-3.25 (m, 3H), 3.18-3.05 (m, 2H), 2.07 (m, 3H), 2.00-1.75 (m, 4H),1.65-1.45 (m, 2H), 1.00 (s, 9H). 4472-[(1-methylpiperidin-4-yloxy)(4-nitrophenyl)methyl]-1H- 165C, B,benzimidazole 210, 165D mp = 90° C.

Example 4482-{(1-methylpiperidin-4-yloxy)[3-(pyridin-3-yloxy)phenyl]methyl}benzothiazole,oxalate

A screw-capped tube is charged with2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole(example 41, 500 mg), copper(I) iodide (9 mg),2,2,6,6-tetramethylheptane-3,5-dione (37 mg), cesium carbonate (701 mg),3-hydroxypyridine (125 mg), powdered 4A molecular sieves (200 mg) andanhydrous N,N-dimethylformamide (1 mL). The tube is evacuated, filledwith argon and sealed. After stirring at 95° C. for 2 days, the mixtureis diluted with ethyl acetate, water and ammonia. After decantation, theaqueous phase is extracted with ethyl acetate. The pooled organicextracts are dried over magnesium sulfate and concentrated under reducedpressure. The residue is purified by chromatography over silica gel(gradient dichloromethane/methanol/ammonia from 98/2/0.5 to 95/5/0.5).to afford the pure base that is then converted into its oxalate salt inacetone to give2-{(1-methylpiperidin-4-yloxy)[3-(pyridin-3-yloxy)phenyl]methyl}benzothiazole,oxalate melting at 78° C.

Example 4492-[(3-bromophenyl)(1-methylpyrrolidin-3-ylmethoxy)methyl]-5-fluoro-1H-benzimidazole,oxalate 449A

2-[(3-bromophenyl)(1-methylpyrrolidin-3-ylmethoxy)methyl]-5-fluoro-1H-benzimidazoleis prepared from 3-bromophenyl(5-fluoro-1H-benzimidazol-2-yl)methanoland pyrrolidin-3-ylmethanol according to general procedures 165C and272A. Conversion into its oxalate salt in acetone gives2-[(3-bromophenyl)(1-methylpyrrolidin-3-ylmethoxy)methyl]-5-fluoro-1H-benzimidazole,oxalate melting at 70° C.

449B

A mixture of (3-bromophenyl)hydroxyacetic acid (3.7 g) and4-fluoro-ortho-phenylenediamine (2 g) in 5N aqueous hydrochloricsolution (3.2 mL) is heated under reflux for 15 h and cooled back toroom temperature. The mixture is basified with concentrated sodiumhydroxide and extracted with ethyl acetate. The organic phase is thendried over magnesium sulfate and concentrated under reduced pressure.The residue is purified by chromatography over silica gel (gradientdichloromethane/methanol/ammonia from 98/2/0.5 to 90/10/0.5) to affordthe pure 3-bromophenyl(5-fluoro-1H-benzimidazol-2-yl)methanol.

Example 4554-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]aniline

To a solution of2-[(1-methylpiperidin-4-yloxy)(4-nitrophenyl)methyl]-1H-benzimidazole(example 447, 200 mg) in methanol (5 mL) and a solution of 5Nhydrochloric acid in isopropanol (0.2 mL) is added 10% palladium oncarbon (50 mg). The flask is evacuated and filled with hydrogen(balloon) and stirred overnight at room temperature. The reactionmixture is filtered on celite and the solvents are evaporated underreduced pressure to dryness. The residual solid is triturated twice withdiethyl ether and the solid is filtered and dry to afford4-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]anilinehydrochloride as a cream-colored solid melting at 185° C.

The following example is made using the same method:

Example Product mp 456 4-[(1H-benzimidazol-2-yl)(piperidin-4- 190° C.yloxy)methyl]aniline, hydrochloride

The following example are made using the method of example 436

Example Product 459N-(2-amino-ethyl)-2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetamide ¹H NMR:7.70-7.52 (m, 2H), 7.50-6.90 (m, 7H), 5.85 (s, 1H), 4.75 (s, 2H),3.85-3.45 (m, 3H), 3.45-3.30 (m, 1H), 3.25-3.05 (m, 1H), 2.80-2.60 (m,3H), 2.57-2.42 (m, 1H), 2.25 (s, 3H), 2.20-1.95 (m, 3H), 1.90-1.55 (m,3H).

Example 4601-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}-3-trifluoromethylpyrrolidin-3-ol,oxalate

A solution of1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-one(example 443, 170 mg) in tetrahydrofuran (3 mL) is treated with cesiumfluoride (612 mg) and trifluoromethyltrimethylsilane (595 μL). Afterstirring for 2 h, the mixture is hydrolyzed with 1N aqueous hydrochloricacid for one night. The reaction mixture is then concentrated underreduced pressure and the residue purified by chromatography over silicagel (dichloromethane/methanol/ammonia 98/2/0.5) to afford the pure basethat is then converted into its oxalate salt in acetone to give1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}-3-trifluoromethylpyrrolidin-3-ol,oxalate. 1H NMR of the base (CDCl3): 7.96 (d, 1H), 7.86 (d, 1H),7.45-7.20 (m, 3H), 6.91 (d, 1H), 6.73 (s, 1H), 6.51 (d, 1H), 5.85 (s,1H), 3.77-3.30 (m, 5H), 2.69 (m, 2H), 2.36 (m, 1H), 2.25 (s, 3H),2.20-1.70 (m, 7H).

Example 4682-[[3-(4,5-dihydro-1H-imidazol-2-ylmethylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole

To a solution of triphenylphosphine oxide (2.2 mmoles) in 4 mL CH₂Cl₂cooled at 0° C. is added dropwise trifluoromethanesulfonyl anhydride(310 mg, 1.1 mmoles). The reaction mixture is stirred at 0° C. for 30minutes, then a solution ofN-(2-aminoethyl)-2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetamide(Example 436) (250 mg, 0.55 mmole) in 2 mL CH₂Cl₂ is added dropwise. Thereaction mixture is allowed to reach room temperature and stirred for1.5 h. The organic phase is washed with 1N sodium hydroxide solution,then dried over magnesium sulfate and concentrated. The residue ispurified by chromatography on silica gel (gradientdichloromethane/methanol/ammonia from 100/0/0 to 80/20/2). The residueis then dissolved in acetone and one equivalent of oxalic acid is added.Acetone is removed under reduced pressure to afford2-[[3-(4,5-dihydro-1H-imidazol-2-ylmethylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazolemelting at 62° C. (déc.); MS, [M+H]⁺=436.1.

The following example is made using the same method

Example Product mp 463 2-[[3-(4,5-dihydro-1H-imidazol-2- 80° C.ylmethylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole

Example 4692-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5,6-difluoro-1H-benzimidazole469A

2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5,6-difluoro-1H-benzimidazoleis prepared from3-bromophenyl(5,6-difluoro-1H-benzimidazol-2-yl)methanol according togeneral procedure 272A, solid melting at 70° C.

469B

A mixture of (3-bromophenyl)hydroxyacetic acid (809 mg) and4,5-difluoro-ortho-phenylenediamine (500 mg) in 5N aqueous hydrochloricsolution (2 mL) is heated under reflux for 15 h and cooled back to roomtemperature. The mixture is basified with concentrated sodium hydroxideand extracted with ethyl acetate. The organic phase is then dried overmagnesium sulfate and concentrated under reduced pressure. The residueis purified by trituration in dichloromethane to afford the pure3-bromophenyl(5,6-difluoro-1H-benzimidazol-2-yl)methanol.

Example 4722-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1-methyl-1H-benzimidazole,dioxalate

A solution of2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole(example 51, 260 mg) in anhydrous acetonitrile (10 mL) is treated with60% sodium hydride (47 mg) for 1 h at room temperature. The mixture isthen cooled to 0° C. and iodomethane (36 μL) is introduced. Afterstirring for 15 h, dilution with water and extraction with ethylacetate, the organic phase is dried over magnesium sulfate andconcentrated under reduced pressure. The residue is purified bychromatography over silica gel (gradientdichloromethane/methanol/ammonia from 95/5/0.5 to 90/10/0.5) to affordthe pure base that is then converted into its dioxalate salt in acetoneto give2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1-methyl-1H-benzimidazole,dioxalate, melting at 76° C.

Example 4792-amino-5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}-1,5-dihydroimidazol-4-one479A2-amino-5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}-1,5-dihydroimidazol-4-one

To a solution of3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-2-(N,N′-bis-tert-butoxycarbonyl)guanidinopropionicacid methyl ester (260 mg) in dichloromethane (2.6 mL) is added dropwisetrifluoroacetic acid (1 mL). The reaction mixture is stirred at roomtemperature for 28 h.

Solvents are removed under reduced pressure. The residue is basified byadding 1N sodium hydroxide, and the solution is evaporated to dryness.The residue is purified by chromatography on silica gel (gradientdichloromethane/methanol/ammonia from 90/10/0 to 90/10/1). The residualsolid is triturated in hot ethyl acetate, cooled down to roomtemperature and filtered. The solid is washed with ethyl acetate; thendried to afford2-amino-5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl-methyl}-1,5-dihydroimidazol-4-one.

MS, [M+H]⁺=465.1; [M+Na]⁺=487.1.

479B3-{3-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-2-(N,N′-bis-tert-butoxycarbonyl)guanidinopropionicacid methyl ester

The compound is synthesized from Example 479C using the method describedat example 307A; mixture of diastereomers. ¹H NMR: 11.35 and 11.13 (sl,1H), 10.25 and 10.06 (sl, 1H), 9.04 and 8.90 (d, 1H, J=7.5 Hz),7.82-7.70 (m, 2H), 7.52-7.18 (m, 6H), 5.89 and 5.84 (s, 1H), 5.58-5.30(m, 1H), 5.25-5.90 (m, 1H), 4.65-4.40 (m, 1H), 3.82-3.05 (m, 6H),2.95-2.75 (m, 2H), 2.38 (sl, 3H), 2.252-1.60 (m, 6H), 1.60-1.30 (m,18H).

479C2-Amino-3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propionicacid methyl ester

The compound is synthesized from example 479D using the method describedin example 437B; mixture of diastereomers. ¹H NMR: 9.74 and 9.67 (sl,1H), 7.80-7.55 (m, 2H), 7.48-7.15 (m, 7H), 5.84 (s, 1H), 3.75-3.50 (m,3H), 3.42-3.15 (m, 3H), 2.90-2.70 (m, 2H), 2.40-2.15 (m, 5H), 2.10-1.70(m, 6H).

479 D3-{3-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-2-tert-butoxycarbonylaminopropionicacid methyl ester

The compound is synthesized from2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole(example 72A) and N-Boc-Cysteine methyl ester using the method describedin example 150; mixture of diastereomers. ¹H NMR: 10.66 and 9.83 (sl,1H), 7.90-7.70 (m, 2H), 7.50-7.35 (m, 2H), 7.35-7.18 (m, 5H), 5.87 and5.85 (s, 1H), 5.58-5.30 (m, 1H), 4.65-4.40 (m, 1H), 3.70-3.20 (m, 6H),2.82-2.62 (m, 2H), 2.28 and 2.26 (s, 3H), 2.22-1.65 (m, 6H), 1.53 and1.45 (s, 9H).

Example 4812-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5,6,7-trifluoro-1H-benzimidazole481A

2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5,6,7-trifluoro-1H-benzimidazole,solid melting at 140° C., is prepared according to general procedure165C from2-[(3-bromophenyl)(piperidin-4-yloxy)methyl]-5,6,7-trifluoro-1H-benzimidazole.

481B

To a solution of4-[(3-bromophenyl)carboxymethoxy]piperidine-1-carboxylic acid tert-butylester (general procedure 165D+saponification)(1 g) in acetonitrile (10mL) are added 3,4,5-trifluorobenzene-1,2-diamine (470 mg),2-chloro-1-methylpyridinium iodide (802 mg) and dropwisediisopropylethylamine (1.1 mL). The reaction mixture is stirred at roomtemperature for 2 hours. Solvent is removed under reduced pressure andthe residue diluted with ethyl acetate. The organic phase is washed withwater, dried over magnesium sulfate and concentrated under reducedpressure. The residue is purified by chromatography over silica gel(gradient dichloromethane/methanol/ammonia from 98/2/0.2 to 90/10/1) toget4-[(6-amino-2,3,4-trifluorophenylcarbamoyl)(3-bromophenyl)methoxy]piperidine-1-carboxylicacid tert-butyl ester. This intermediate is dissolved in acetic acid (15mL) and the reaction mixture is refluxed for 3 hours. Acetic acid isremoved under reduced pressure. Water is added to the residue and thesolution is basified by adding a solution of saturated sodiumhydrogencarbonate to pH 10. The aqueous phase is extracted with ethylacetate. The pooled organic extracts are dried over magnesium sulfateand concentrated under reduced pressure. The residue is purified bychromatography over silica gel (gradientdichloromethane/methanol/ammonia from 98/2/0.2 to 90/10/1) to yield2-[(3-bromophenyl)(piperidin-4-yloxy)methyl]-5,6,7-trifluoro-1H-benzimidazole.

Example 4971-(2-ethoxyethyl)-2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,dioxalate

A solution of2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole(example 51, 260 mg) in anhydrous acetonitrile (10 mL) is treated with60% sodium hydride (47 mg) for 30 min at room temperature.1-Bromo-2-ethoxyethane (84 μL) is then introduced. After warming at 60°C. for 8 h, dilution with water and extraction with diethylether, theorganic phase is dried over magnesium sulfate and concentrated underreduced pressure. The residue is purified by chromatography over silicagel (gradient dichloromethane/methanol/ammonia from 98/2/0.5 to95/5/0.5) to afford the pure base that is then converted into itsdioxalate salt in acetone to give1-(2-ethoxyethyl)-2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,dioxalate, melting at 88° C.

Example 505 505A5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzylidene}-2-iminoimidazolidin-4-one

To a solution of3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-benzaldehyde(example 505C, 200 mg) in a mixture of ethanol-water (8:2) (3 mL) isadded thiohydantoin (70 mg) and piperidine (57 μL). The reaction mixtureis heated at 55° C. for 5 h. Ethanol is removed under reduced pressure.Water is added and the reaction mixture is extracted by ethyl acetate.The organic phase is washed by water, then dried over magnesium sulfateand concentrated. The residue is purified by chromatography on silicagel (gradient dichloromethane/methanol from 95/5 to 90/10). The residueis dissolved in methanol (6 mL) and 30% solution of aqueous ammonia (1.1mL) and tert-butylhydroperoxide (90 μL) are added. The reaction mixtureis stirred at room temperature for two days. The reaction mixture isevaporated to dryness. The residue is purified by chromatography onsilica gel (gradient dichloromethane/methanol/ammonia from 90/10/0.1 to70/30/0.1) to give5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzylidene}-2-iminoimidazolidin-4-one.MS, [M+H]⁺=431.1; [M+Na]⁺=453.1

505B3-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzaldehyde

To a solution of3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-benzonitrile(example 172, 740 mg) in 80% aqueous formic acid (3 mL) is addedplatinum(IV) oxide (48 mg). The reaction mixture is heated at 60° C. for7 h, then at room temperature for 2 days. As the reaction is notcomplete, 80% aqueous formic acid (3 mL) and platinum (IV) oxide (48 mg)are added and the reaction mixture is heated at 60° C. overnight. Wateris added and the reaction mixture is filtered on celite. The phase isbasified by adding a solution of 1N sodium hydroxide and extracted byethyl acetate. The organic phase is washed by water, then dried overmagnesium sulfate and concentrated to give3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzaldehyde.¹H NMR: 9.99 (s, 1H), 9.67 (sl, 1H), 8.01 (s, 1H), 7.85-7.65 (m, 2H),7.60-7.40 (m, 2H), 7.32-7.15 (m, 3H), 5.95 (s, 1H), 3.65-3.50 (m, 1H),2.82-2.65 (m, 2H), 2.26 (s, 3H), 2.20-1.65 (m, 6H).

Example 507

4-{3-[(1H-benzimidazol-2-yl)(1-methylazetidin-3-ylmethoxy)methyl]-phenylsulfanyl}butylamine,oxalate. Compound made from example 506 using methods described inexamples 150, 432. ¹H NMR (methanol-d₄)(base): 7.65-7.40 (m, 3H),7.40-7.10 (m, 5H), 5.69 (s, 1H), 3.785-3.40 (m, 4H), 3.40-3.10 (m, 5H),2.44 (s, 3H), 1.80-1.45 (m, 3H), 1.35-1.10 (m, 2H), 1.00-1.75 (m, 1H).

Example 5252-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzoxazole,oxalate 525A

2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzoxazole,oxalate (solid melting at 103° C.) is prepared according to generalprocedure 272A.

525B

A mixture of (2-fluoro-5-trifluoromethoxyphenyl)hydroxyacetic acid(prepared according to 72C) (2.4 g), ortho-aminophenol (1.03 g) inxylene (25 mL) is refluxed for 4 h with a Dean-Stark apparatus andconcentrated under reduced pressure. Purification by chromatography onsilica gel (gradient dichloromethane/methanol/ammonia from 100/0/0 to98/2/0.5) to afford the purebenzoxazol-2-yl(2-fluoro-5-trifluoromethoxyphenyl)methanol.

Example 528 528A2-[(1-methylpiperidin-4-yloxy)(3-methylsulfanylmethylphenyl)methyl]-1H-benzimidazole

To a solution of{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}methanol(example 528B, 320 mg) in dichloromethane (3 mL) is added triethylamine(0.16 mL). The reaction mixture is cooled to 0° C., and methanesulfonylchloride (84 μL) is added dropwise. The reaction mixture is stirred atroom temperature for 3 h, then cooled to 0° C. and sodium thiomethoxide(191 mg) is added. After one night at room temperature, methanol (2 mL)is added to help solubilizing the suspension. The reaction mixture isstirred at room temperature overnight. Water is added and the aqueousphase is extracted by dichloromethane. The organic phase is washed bywater, then dried over magnesium sulfate and concentrated. The residueis purified by chromatography on silica gel (gradientdichloromethane/methanol/ammonia from 90/10/0 to 90/10/0.1 then80/20/0.1), followed by a purification by preparative thin-layerchromatography (dichloromethane/methanol/ammonia from 90/10/0.1) to give2-[(1-methylpiperidin-4-yloxy)(3-methylsulfanylmethylphenyl)methyl]-1H-benzimidazole.MS, [M+H]⁺=382.1;

528B{3-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}methanol

To a solution of3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzaldehyde(example 505B, 310 mg) in methanol (4 mL) is added portionwise sodiumborohydride (50 mg). The reaction mixture is stirred at room temperaturefor 15 minutes then heated at reflux for 3 h. Methanol is removed underreduced pressure. Water is added and the aqueous phase is extracted byethyl acetate. The organic phase is washed by water, then dried overmagnesium sulfate and concentrated to give{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-phenyl}methanol.¹H NMR: 9.85 (sl, 1H), 7.78-7.65 (m, 1H), 7.50-7.12 (m, 7H), 5.87 (s,1H), 4.64 (s, 2H), 3.62-3.45 (m, 1H), 2.78-2.58 (m, 2H), 2.22 (s, 3H),2.15-1.50 (m, 6H).

Example 530 530A2-[(3-bromophenyl)(1-methyl-1,2,3,6-tetrahydropyridin-4-ylsulfanyl)methyl]-1H-benzimidazole

To a solution of 1,2-phenylenediamine (213 mg) in toluene (2 mL) isadded dropwise a solution of 2M trimethylaluminium in toluene (1 ml).The reaction mixture is heated at 75° C. for 2 hours then a solution of(3-bromophenyl)(1-methyl-1,2,3,6-tetrahydropyridin-4-ylsulfanyl)aceticacid methyl ester (example 530B, 358 mg) in toluene (2 mL) is added, andthe heating is continued at 75° C. for 3 hours. Water is added and thereaction mixture is made alkaline by adding 1N sodium hydroxide. Theaqueous phase is extracted by ethyl acetate. The organic phase is washedby water, brine, then dried over magnesium sulfate and concentrated. Theresidue is the dissolved in acetic acid (5 mL) and the reaction mixtureis refluxed for 3 hours. The solvent is removed under reduced pressure.Water is added and the reaction mixture is made alkaline by adding 2Nsodium hydroxide. The aqueous phase is extracted by ethyl acetate. Theorganic phase is washed by water, brine, then dried over magnesiumsulfate and concentrated. The residual solid is triturated withacetonitrile, filtered and the solid is washed with diethyl ether togive2-[(3-bromophenyl)(1-methyl-1,2,3,6-tetrahydropyridin-4-ylsulfanyl)methyl]-1H-benzimidazolemelting at 189° C.

530B(3-Bromophenyl)(1-methyl-1,2,3,6-tetrahydropyridin-4-ylsulfanyl)aceticacid methyl ester

To a solution of4-[(3-bromophenyl)methoxycarbonylmethylsulfanyl]-1-methylpyridiniumiodide (example 530C, 480 mg) in methanol (5 mL) is added portionwisesodium borohydride (2 equivalents). The mixture is refluxed for one hourthen concentrated to dryness. Water is added and the aqueous phase isextracted by ethyl acetate. The organic phase is washed by water, brine,then dried over magnesium sulfate and concentrated to give(3-Bromophenyl)(1-methyl-1,2,3,6-tetrahydropyridin-4-ylsulfanyl)aceticacid methyl ester. ¹H NMR: 7.62 (s, 1H), 7.50-7.35 (m, 2H), 7.30-7.15(m, 1H), 5.75 (sl, 1H), 4.77 (s, 1H), 3.76 (s, 3H), 3.10-2.98 (m, 2H),2.68-2.55 (m, 2H), 2.45-2.25 (m, 5H).

530C 4-[(3-Bromophenyl)methoxycarbonylmethylsulfanyl]-1-methylpyridiniumiodide

To a solution of (3-bromophenyl)(pyridin-4-ylsulfanyl)acetic acid methylester (example 530D, 2.2 g) in acetonitrile (50 mL) is added iodomethane(1.2 equivalent) and the mixture is stirred over-the-weekend at roomtemperature. The solid is filtered and washed with diethyl ether to give4-[(3-Bromophenyl)methoxycarbonylmethylsulfanyl]-1-methylpyridiniumiodide. ¹H NMR (dmso-d₆): 8.75-8.65 (m, 2H), 7.98-7.88 (m, 2H), 7.78 (s,1H), 7.63-7.51 (m, 2H), 7.42-7.30 (m, 1H), 6.20 (s, 1H), 4.13 (s, 3H),3.70 (s, 3H).

530 D (3-Bromophenyl)(pyridin-4-ylsulfanyl)acetic acid methyl ester

To a solution of dimethylsulfoxonium ylide and 3-bromophenylacetic acidmethyl ester (example 530E, 3 g) in dichloroethane (50 mL) are added4-mercaptopyridine (2 equivalents) and [Ir(COD)Cl]₂ (20 mg). Thereaction mixture is refluxed overnight then concentrated to drynessunder reduced pressure. The residue is purified by chromatography onsilica gel (heptane/ethyl acetate 1/1) to give(3-Bromophenyl)(pyridin-4-ylsulfanyl)acetic acid methyl ester. ¹H NMR:8.50-8.35 (m, 2H), 7.68 (s, 1H), 7.55-7.45 (m, 2H), 7.35-7.20 (m, 1H),7.20-7.05 (m, 2H), 5.08 (s, 1H), 3.77 (s, 3H).

530E Dimethylsulfoxonium ylide of 3-Bromophenylacetic acid methyl ester

To a solution of (3-bromophenyl)diazoacetic acid methyl ester(synthesized according to the method described in example 165E, 7.5 g)in dimethylsulfoxide (35 mL) is added copper(II)cyanide (150 mg), andthe mixture is heated at 60° C. for 1 h, with evolution of nitrogen. Thesolvent is removed under reduced pressure. Water is added and thereaction mixture is extracted by ethyl acetate. The organic phase iswashed by water, brine, then dried over magnesium sulfate andconcentrated. The residual solid is triturated with diisopropyl ether,filtered and dried to give the dimethylsulfoxonium ylide of3-bromophenylacetic acid methyl ester. ¹H NMR: 7.47 (s, 1H), 7.45-7.35(m, 1H), 7.30-7.12 (m, 2H), 3.63 (s, 3H), 3.45 (s, 6H)

Example 5332-[(2-fluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,enantiomer B

A solution of racemic2-[(2-fluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole(10 mg/mL) in a mixture of heptane/isopropanol (90/10) containingdiethylamine (0.1%) is injected (30×100 μL) onto an analytical ChiralpakAD-H, 250×4.6 mm column. Elution is performed with a mixture ofheptane/isopropanol (90/10) containing diethylamine (0.1%) at a flow of1 mL/min. Products are detected at 210 nm. The enantiomer B has aretention time of 13.2 min. Collection affords2-[(2-fluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazoleenantiomer B with a chromatographic enantiomeric purity of 97.4%.

Example 5342-[(2,6-difluoro-3-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole534A

2-[(2,6-Difluoro-3-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole(solid melting at 185° C.) is prepared according to general procedure172A from (1H-benzimidazol-2-yl)(2,6-difluoro-3-methoxyphenyl)methanol.

534B

A solution of(2,6-difluoro-3-methoxyphenyl)[1-(2-trimethylsilylethoxymethyl)-1H-benzimidazol-2-yl]methanol(1.4 g) in tetrahydrofuran (20 mL) is refluxed for 15 h withtetrabutylammonium fluoride (10 mL of a 1M solution in tetrahydrofuran).The mixture is then concentrated under reduced pressure and purified bychromatography over silica gel (gradient dichloromethane/methanol from100/0 to 95/5) to afford the pure(1H-benzimidazol-2-yl)-(2,6-difluoro-3-methoxyphenyl)methanol.

534C

To a solution of 2,4-difluoro-1-methoxybenzene (156 mg) intetrahydrofuran (5 mL) at −78° C. is added a 2M solution of lithiumdiisopropylamide in THF (540 μL). After stirring for 45 min a solutionof 1-(2-trimethylsilylethoxymethyl)-1H-benzimidazole-2-carbaldehyde(which can be prepared according to US2003/220341 or U.S. Pat. No.6,476,041 for example) (300 mg) in tetrahydrofuran (5 mL) is added at−78° C. and the reaction mixture allowed to warm to room temperature.After hydrolysis with aqueous saturated ammonium chloride and extractionwith ethyl acetate, the organic phase is dried over magnesium sulfateand concentrated under reduced pressure. The residue is purified bychromatography over silica gel (gradient dichloromethane/methanol from100/0 to 95/5) to afford(2,6-difluoro-3-methoxyphenyl)[1-(2-trimethylsilylethoxymethyl)-1H-benzimidazol-2-yl]methanol.

Example 549 ethyl(6-{3-[(1-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)carbamate,oxalate

To a cooled solution of6-{3-[(1-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynylamine(example 480, 22 mg) in dichloromethane is added ethyl chloroformate (1eq). After stirring at room temperature, the organic phase is washedwith aqueous sodium hydroxide, dried over magnesium sulfate andconcentrated under reduced pressure. The residue is purified bychromatography over silica gel (gradient dichloromethane/methanol from100/0 to 90/10) to afford the pure base that is then converted into itsoxalate salt in acetone to give ethyl(6-{3-[(1-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)carbamate,oxalate melting at 90° C.

Example 5502-[(1H-indol-6-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,oxalate 550A

2-[(1-Benzenesulfonyl-1H-indol-6-yl)(1-methyl-piperidin-4-yloxy)methyl]-1H-benzimidazole(150 mg) and sodium hydroxide (excess) in methanol are refluxed for 3 h.The reaction mixture is then concentrated under reduced pressure,diluted with water and extracted with dichloromethane. The organic phaseis dried over magnesium sulfate and concentrated under reduced pressure.The residue is purified by chromatography over silica gel (gradientdichloromethane/methanol/ammonia from 100/0/0 to 80/20/2) to afford thepure base that is then converted into its oxalate salt in acetone togive2-[(1H-indol-6-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,oxalate, melting at 170° C.

550B

2-[(1-Benzenesulfonyl-1H-indol-6-yl)(1-methyl-piperidin-4-yloxy)methyl]-1H-benzimidazoleis prepared according to general procedures 172A and 172B from1-benzenesulfonyl-1H-indole-6-carbaldehyde.

Example 5562-[benzo[b]thiophen-6-yl(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,oxalate 556A

2-[Benzo[b]thiophen-6-yl(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,oxalate melting at 160° C. is prepared according to general procedures272A and 534B frombenzo[b]thiophen-6-yl[1-(2-trimethylsilylethoxymethyl)-1H-benzimidazol-2-yl]methanol.

556B

To a suspension of magnesium (86 mg) in tetrahydrofuran is added asolution of 6-bromobenzo[b]thiophene (which can be prepared according toWO2006/107784) (500 mg) in tetrahydrofuran. After reflux for 3 h, asolution of1-(2-trimethylsilylethoxymethyl)-1H-benzimidazole-2-carbaldehyde (whichcan be prepared according to US2003/220341 or U.S. Pat. No. 6,476,041for example) (635 mg) in tetrahydrofuran is added to the Grignardreagent at room temperature. After stirring for 12 h, the reactionmixture is treated with diluted hydrochloric acid and the organic phaseis dried over magnesium sulfate and concentrated under reduced pressure.The residue is purified by chromatography over silica gel (gradientdichloromethane/methanol from 100/0 to 90/10) to affordbenzo[b]thiophen-6-yl[1-(2-trimethylsilylethoxymethyl)-1H-benzimidazol-2-yl]methanol.

Example 5592-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,enantiomer B

A solution of racemic2-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole(example 523) (10 mg/mL) in a mixture of heptane/isopropanol (90/10)containing diethylamine (0.1%) is injected (30×100 μL) onto ananalytical Chiralpak AD-H, 250×4.6 mm column. Elution is performed witha mixture of heptane/isopropanol (90/10) containing diethylamine (0.1%)at a flow of 1 mL/min. Products are detected at 210 nm. The enantiomer Bhas a retention time of 13.9 min. Collection affords2-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,enantiomer B with a chromatographic enantiomeric purity of 99.3%

Example 5612-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol 561A

2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol (solidmelting at 118-120° C.) is prepared from2-[(1H-benzimidazol-2-yl)hydroxymethyl]phenol according to generalprocedure 1A.

561B

To a solution of 1-pyrrolidin-1-ylmethyl-1H-benzimidazole (6 g) intetrahydrofuran (40 mL) at −78° C., is added a 2.3M solution ofbutyllithium in hexanes (13 mL). The mixture is stirred for 25 minutes.Salicaldehyde (1.82 g) is then dropwise introduced at −78° C. After 1 hat the same temperature, the mixture is allowed to warm to roomtemperature and hydrolyzed with aqueous saturated ammonium chloride.After 1 h, the mixture is extracted with ethyl acetate. Pooled extractsare washed with brine, dried over magnesium sulfate and concentratedunder reduced pressure. The residue is purified by trituration indichloromethane to afford 2-[(1H-benzimidazol-2-yl)hydroxymethyl]phenol.

Example 5622-[(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylimino)phenylmethyl]phenol

A mixture of6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylamine,oxalate (example 557, 70 mg), 2-hydroxybenzophenone (30 mg) in ethanol(4 mL) is refluxed for 4 h. The mixture is then cooled, diluted withwater and extracted with ethyl acetate. Pooled extracts are dried overmagnesium sulfate and concentrated under reduced pressure. The residueis purified by chromatography over silica gel (gradientdichloromethane/methanol/ammonia from 100/0/0 to 90/10/0.5) to afford2-[(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylimino)phenylmethyl]phenol.TLC (Eluent: CH₂Cl₂/MeOH/NH₄OH 95/5/0.5) Rf=0.15.

Example 5635-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylimino)-2-methylcyclopent-1-enol

A mixture of6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylamine,oxalate (example 557, 50 mg), 3-methyl-1,2-cyclopentanedione (11.8 mg)in ethanol (2 mL) is refluxed for 2 h. The mixture is then cooled,diluted with water and 1N sodium hydroxide and extracted with ethylacetate. Pooled extracts are dried over magnesium sulfate andconcentrated under reduced pressure. The residue is purified bychromatography over silica gel (gradientdichloromethane/methanol/ammonia from 100/0/0.5 to 95/5/0.5) to afford5-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylimino)-2-methylcyclopent-1-enol.TLC (Eluent: CH₂Cl₂/MeOH/NH₄OH 95/5/0.5) Rf=0.30.

Example 5642-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,enantiomer B

Resolution of racemic2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole(example 78) with (1R)-(−)-10-camphorsulfonic acid (0.45 eq) in ethylacetate affords after several recrystallizations enantiopure2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,enantiomer B (solid melting at 85° C.). HPLC analysis: analyticalChiralpak AD-H, 250×4.6 mm column. Elution is performed with a mixtureof heptane/isopropanol (90/10) containing diethylamine (0.1%) at a flowof 1 mL/min. The enantiomer B has a retention time of 10.4 min.

Example 5655-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine,enantiomer A

5-{3-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine,enantiomer A (melting at 84° C.) is prepared according to generalprocedures 194 and 189 from2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,enantiomer A (prepared according example 564 with(1S)-(+)-camphorsulfonic acid).

Example 5665-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine,enantiomer B

5-{3-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine,enantiomer B (melting at 82° C.) is prepared according to generalprocedures 194 and 189 from2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,enantiomer B (example 564).

Example 5672-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole,enantiomer A

Resolution of racemic2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazolewith (1S)-(+)-10-camphorsulfonic acid (0.5 eq) in ethyl acetate affordsafter several recrystallizations2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole,enantiomer A (solid melting at 89° C.). HPLC analysis: analyticalChiralpak AD-H, 250×4.6 mm column. Elution is performed with a mixtureof heptane/isopropanol (90/10) containing diethylamine (0.1%) at a flowof 1 mL/min. The enantiomer A has a retention time of 8.2 min.e.e.=93.5%

Example 5682-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole,enantiomer B

Resolution of racemic2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazolewith (1R)-(−)-10-camphorsulfonic acid (0.5 eq) in ethyl acetate affordsafter several recrystallizations2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole,enantiomer B (solid melting at 89° C.). HPLC analysis: analyticalChiralpak AD-H, 250×4.6 mm column. Elution is performed with a mixtureof heptane/isopropanol (90/10) containing diethylamine (0.1%) at a flowof 1 mL/min. The enantiomer B has a retention time of 10.3 min.e.e.=95.5%

Example 5782-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-methylphenol

A mixture of 2-[(1H-benzimidazol-2-yl)hydroxymethyl]-4-methylphenol(prepared according to procedure 561B) (360 mg), methanesulfonic acid(500 μL) and 1-methyl-4-piperidinol (500 mg) in 1,2-dichloroethane (20mL) and N-methylpyrrolidinone (2 mL) is warmed at 90° C. for 2 h. Aftercooling at 0° C., the mixture is diluted with water and dichloromethaneand concentrated sodium hydroxide slowly added up to pH 9. Organic phaseis then dried over magnesium sulfate and concentrated under reducedpressure. The residue is purified by chromatography over silica gel(gradient dichloromethane/methanol/ammonia from 100/0/0.5 to 80/20/0.5)to afford2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-methylphenol,melting at 151° C.

For the other examples prepared according this general procedure, it canbe advantageous to rise the temperature progressively after having mixedthe different reagents and to observe when etherification occurs. Oncethe right temperature has been found, reaction may be continued up toadequate conversion. Use of N-methylpyrrolidinone can be optionaldepending of the solubility of the mixture. Additional equivalents ofmethanesulfonic acid can be used for a better conversion if necessary.

Example 6262-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenolenantiomer A

2-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenolenantiomer A is prepared by separation on Chiralpak AD-H from racemic2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol(example 561). HPLC analysis: Chiralpak AD-H, 250×4.6 mm column. Elutionis performed with a mixture of heptane/isopropanol (90/10) containingdiethylamine (0.1%) at a flow of 1 mL/min. The enantiomer A has aretention time of 18.8 min. e.e.=100%

Example 6272-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenolenantiomer B

2-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenolenantiomer B is prepared by separation on Chiralpak AD-H from racemic2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol(example 561). HPLC analysis: Chiralpak AD-H, 250×4.6 mm column. Elutionis performed with a mixture of heptane/isopropanol (90/10) containingdiethylamine (0.1%) at a flow of 1 mL/min. The enantiomer B has aretention time of 34.3 min. e.e.=100%

Example 6286-[(1Hbenzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-3-methylphenolenantiomer A

By analogy with example 626 from racemic6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-3-methylphenol(example 601). HPLC analysis: Chiralpak AD-H, 250×4.6 mm column. Elutionis performed with a mixture of heptane/isopropanol (90/10) containingdiethylamine (0.1%) at a flow of 1 mL/min. The enantiomer A has aretention time of 15.8 min.

Example 6296-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-3-methylphenolenantiomer B

By analogy with example 627 from racemic6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-3-methylphenol(example 601). HPLC analysis: Chiralpak AD-H, 250×4.6 mm column. Elutionis performed with a mixture of heptane/isopropanol (90/10) containingdiethylamine (0.1%) at a flow of 1 mL/min. The enantiomer B has aretention time of 19.9 min.

Example 6306-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2,3-difluorophenolenantiomer A

By analogy with example 626 from racemic6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2,3-difluorophenol(example 625). HPLC analysis: Chiralpak AD-H, 250×4.6 mm column. Elutionis performed with a mixture of heptane/isopropanol (90/10) containingdiethylamine (0.1%) at a flow of 1 mL/min. The enantiomer A has aretention time of 13.4 min.

Example 6316-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2,3-difluorophenolenantiomer B

By analogy with example 627 from racemic6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2,3-difluorophenol(example 625). HPLC analysis: Chiralpak AD-H, 250×4.6 mm column. Elutionis performed with a mixture of heptane/isopropanol (90/10) containingdiethylamine (0.1%) at a flow of 1 mL/min. The enantiomer B has aretention time of 15.3 min.

Further examples can be prepared according to the described generalmethods:

General Example Product methods Melting point 4425-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 194, 189, 425 139° C.yloxy)methyl]-4-fluorophenyl}pent-4-ynylamine, dioxalate 4533-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 194, 432A,  91° C.yloxy)methyl]phenoxy}cyclopentylamine, oxalate 258 4542-{[3-(3-fluoropyrrolidin-1-yl)phenyl](1- 423B 103° C.methylpiperidin-4-yloxy)methyl}benzothiazole, oxalate 4625-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1- 194, 189, 449 200° C.methylpyrrolidin-3-ylmethoxy)methyl]phenyl}pent-4- ynylamine, oxalate464 2-[(3-bromophenyl)(1-methylpyrrolidin-3- 165C, 1A, 1B  68° C.ylmethoxy)methyl]benzothiazole, oxalate (one epimer) 4652-[(3-bromophenyl)(1-methylpyrrolidin-3- 165C, 1A, 1B  68° C.ylmethoxy)methyl]benzothiazole, oxalate (50/50 mixture of two epimers)466 2-{(1-methylpiperidin-4-yloxy)[3- 249, 258  70° C.(octahydrocyclopenta[c]pyrrol-5- yloxy)phenyl]methyl}benzothiazole,dioxalate 467 (1-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 249, 423B216° C. yloxy)methyl]phenyl}pyrrolidin-3-yl)methylamine, dioxalate 4704-{3-[(5,6-difluoro-1H-benzimidazol-2-yl)(1- 150, 469  60° C.methylpiperidin-4- yloxy)methyl]phenylsulfanyl}butan-1-ol 4712-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 194, 432A, 126° C.yloxy)methyl]phenyl}octahydrocyclopenta[c]pyrrol- 423B 5-ylamine,dioxalate 475 2-{[3-(3-fluoropropoxy)phenyl](1-methylpiperidin-4- 272A,272B 106° C. yloxy)methyl}-1H-benzimidazole, oxalate 4762-{[3-(2-fluoroethoxy)phenyl](1-methylpiperidin-4- 272A, 272B 136° C.yloxy)methyl}-1H-benzimidazole, oxalate 4774-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 194, 432A, 95° C.yloxy)methyl]phenoxy}cyclohexylamine, oxalate 258 4806-{3-[(1-methyl-1H-benzimidazol-2-yl)(1- 194, 189, 472 113° C.methylpiperidin-4-yloxy)methyl]phenyl}hex-5- ynylamine, dioxalate 4821-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 194, 432A, 145° C.yloxy)methyl]phenyl}pyrrolidin-2-ylmethylamine, 423B oxalate 483(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 249, 423B 115° C.yloxy)methyl]phenyl}pyrrolidin-3-yl)(methyl)amine, oxalate 484(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 423B 106° C.yloxy)methyl]phenyl}pyrrolidin-3-yl)(dimethyl)amine, oxalate 4852-{[3-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2- 423B 131° C.yl)phenyl](1-methylpiperidin-4- yloxy)methyl}benzothiazole, dioxalate486 2-[(2-fluoro-5-methoxyphenyl)(1-methylpiperidin-4- 272A, 272B 105°C. yloxy)methyl]-1H-benzimidazole, oxalate 4873-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 272A, 272B 135° C.yloxy)methyl]-4-fluorophenol, oxalate 4892-{[2-fluoro-5-(2-fluoroethoxy)phenyl](1- 272A, 272B 109° C.methylpiperidin-4-yloxy)methyl}-1H-benzimidazole, oxalate 4902-[(2-fluoro-5-methylphenyl)(1-methylpiperidin-4- 272A, 272B 132° C.yloxy)methyl]-1H-benzimidazole, oxalate 4934-{3-[(1-methylpiperidin-4-yloxy)(5,6,7-trifluoro-1H- 305A, 305B, 110°C. benzimidazol-2- 481 yl)methyl]phenylsulfanyl}butylamine, oxalate 4954-{3-[(5,6-difluoro-1H-benzimidazol-2-yl)(1- 305A, 305B, 180° C.methylpiperidin-4- 469 yloxy)methyl]phenylsulfanyl}butylamine, oxalate500 6-(3-{[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl](1- 194, 189, 497 103°C. methylpiperidin-4-yloxy)methyl}phenyl)hex-5- ynylamine, dioxalate 5016-(3-{[1-(2-methoxyethyl)-1H-benzimidazol-2-yl](1- 194, 189, 497 109° C.methylpiperidin-4-yloxy)methyl}phenyl)hex-5- ynylamine, dioxalate 5082-{[3-(3-fluoropropylsulfanyl)phenyl](1- 150  85° C.methylpiperidin-4-yloxy)methyl}-1H-benzimidazole, dioxalate 5095-fluoro-2-[(2-fluoro-5-trifluoromethoxyphenyl)(1- 272A, 272B  70° C.methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate 5104,5,6-trifluoro-2-[(2-fluoro-5- 272A, 272B  75° C.trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole 511 5,6-difluoro-2-[(2-fluoro-5- 272A,272B  9° C. trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole 5222-{[2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl](1- 272A, 272B 204° C.methylpiperidin-4-yloxy)methyl}-1H-benzimidazole 5232-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin- 272A, 272B 211° C.4-yloxy)methyl]-1H-benzimidazole 5242-[(2-chloro-5-trifluoromethoxyphenyl)(1- 272A, 272B 107° C.methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate 5262-[(2-fluoro-5-trifluoromethoxyphenyl)(1- 272A, 1B  95° C.methylpiperidin-4-yloxy)methyl]benzothiazole, oxalate 5272-[(4-chloro-2,6-difluorophenyl)(1-methylpiperidin-4- 272A, 272B 195° C.yloxy)methyl]-1H-benzimidazole 5297-fluoro-2-[(2-fluoro-5-trifluoromethoxyphenyl)(1- 165C, 165A 135° C.methylpiperidin-4-yloxy)methyl]-1H-benzimidazole, oxalate 5312-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin- 272A, 168B 125° C.4-yloxy)methyl]benzothiazole, oxalate 5322-[(4-chloro-2,6-difluorophenyl)(1-methylpiperidin-4- 272A, 1B 158° C.yloxy)methyl]benzothiazole, oxalate 5352-[(3-ethoxy-2,6-difluorophenyl)(1-methylpiperidin- 534 130° C.4-yloxy)methyl]-1H-benzimidazole 5362-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin- 525 114° C.4-yloxy)methyl]benzoxazole, oxalate 5372-[(1-methylpiperidin-4-yloxy)(4- 272A, 272B  86° C.trifluoromethylphenyl)methyl]-1H-benzimidazole 5402-[(2-fluoro-4-trifluoromethylphenyl)(1- 272A, 272B  91° C.methylpiperidin-4-yloxy)methyl]-1H-benzimidazole 5412-[(2,4-dimethylphenyl)(1-methylpiperidin-4- 272A, 272B 120° C.yloxy)methyl]-1H-benzimidazole 5422-[(3-methoxyphenyl)(1-methylpiperidin-4- 272A, 272B  83° C.yloxy)methyl]-1H-benzimidazole 5432-[chroman-7-yl(1-methylpiperidin-4-yloxy)methyl]- 272A, 272B 128° C.1H-benzimidazole 545 2-[(2-fluoro-4-methylphenyl)(1-methylpiperidin-4-525 110° C. yloxy)methyl]benzoxazole, oxalate 5472-[(3,5-bis-trifluoromethylphenyl)(1-methylpiperidin- 272A, 272B 130° C.4-yloxy)methyl]-1H-benzimidazole, oxalate 5485-fluoro-2-[(2-fluoro-4-methylphenyl)(1- 272A, 272B  90° C.methylpiperidin-4-yloxy)methyl]-1H-benzimidazole 5512-[(2,3-difluoro-4-methylphenyl)(1-methylpiperidin- 272A, 272B  80° C.4-yloxy)methyl]-1H-benzimidazole 5522-[(3-chloro-4-methylphenyl)(1-methylpiperidin-4- 272A, 272B  86° C.yloxy)methyl]-1H-benzimidazole 553 ethyl2-[(2-fluoro-5-trifluoromethoxyphenyl)(1- 549 118° C.methylpiperidin-4-yloxy)methyl]benzimidazole-1- carboxylate, oxalate 5542-[(3-fluoro-4-methylphenyl)(1-methylpiperidin-4- 272A, 272B  92° C.yloxy)methyl]-1H-benzimidazole 5552-[(5-bromo-2-fluorophenyl)(1-methylpiperidin-4- 272A, 272B 232° C.yloxy)methyl]-1H-benzimidazole 5576-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 194, 189, 555 195° C.yloxy)methyl]-4-fluorophenyl}hex-5-ynylamine, oxalate 5585-{4-fluoro-3-[(5-fluoro-1H-benzimidazol-2-yl)(1- 194, 189,  90° C.methylpiperidin-4-yloxy)methyl]phenyl}pent-4- 272A, 272B ynylamine 560ethyl (5-{3-[(1H-benzimidazol-2-yl)(1- 549, 442  87° C.methylpiperidin-4-yloxy)methyl]-4- fluorophenyl}pent-4-ynyl)carbamate569 2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 272A, 561B 185° C.yloxy)methyl]-4-chlorophenol 570 ethyl(5-{4-fluoro-3-[(5-fluoro-1H-benzimidazol-2- 189, 272A,  95° C.yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4- 272B ynyl)carbamate571 2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 272A, 561B 132° C.yloxy)methyl]-4-trifluoromethoxyphenol 5722-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 272A, 561B 142° C.yloxy)methyl]-4-fluorophenol 5732-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 1A, 561B 146° C.yloxy)methyl]-4-methoxyphenol 5742-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 1A, 561B 145° C.yloxy)methyl]-5-methylphenol 5752-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 272A, 561B 145° C.yloxy)methyl]-4-bromophenol 5762-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 272A, 561B 213° C.yloxy)methyl]-4-ethoxyphenol 5772-[(1H-indol-7-yl)(1-methylpiperidin-4-yloxy)methyl]- 550A, 1A, 110° C.1H-benzimidazole 272B 579 2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-272A, 561B 142° C. yloxy)methyl]-4,6-difluorophenol 5802-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 272A, 561B 161° C.yloxy)methyl]-4,6-dichlorophenol 5812-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578 145° C.yloxy)methyl]-6-fluorophenol 5822-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578 129° C.yloxy)methyl]-3-fluorophenol 5832-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 272A, 561B 198° C.yloxy)methyl]-4,5-difluorophenol 5842-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578 140° C.yloxy)methyl]-5-fluorophenol 5852-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578 142° C.yloxy)methyl]-5-chlorophenol 5862-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578 111° C.yloxy)methyl]-6-methylphenol 5872-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578 138° C.yloxy)methyl]-4-methylsulfanylphenol 5882-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578 116° C.yloxy)methyl]-4-ethylsulfanylphenol 5893-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578 140° C.yloxy)methyl]biphenyl-4-ol 5902-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 272A, 561B 139° C.yloxy)methyl]-4-tert-butylphenol 5912-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578 120° C.yloxy)methyl]-4-propylphenol 5922-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578 112° C.yloxy)methyl]-6-methoxyphenol 5932-[(1H-benzimidazol-2-yl)(1-methy-piperidin-4- 578 136° C.yloxy)methyl]-3-fluoro-5-methylphenol 5942-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 272A, 561B 145° C.yloxy)methyl]-3-chlorophenol 5952-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 272A, 561B 144° C.yloxy)methyl]-6-fluoro-4-methylphenol 5962-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 272A, 561B 120° C.yloxy)methyl]-4-benzylphenol 5982-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578 135° C.yloxy)methyl]-4-trifluoromethylphenol 5992-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 272A, 561B 146° C.yloxy)methyl]-4-chloro-6-fluorophenol 6002-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 272A, 561B 146° C.yloxy)methyl]-5-fluoro-3-methylphenol 6016-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 272A, 561B 148° C.yloxy)methyl]-2-fluoro-3-methylphenol 6026-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578 152° C.yloxy)methyl]indan-5-ol 6032-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578 120° C.yloxy)methyl]-4-propoxyphenol 6042-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 272A, 561B 130° C.yloxy)methyl]-4-(1-methyl-1-phenylethyl)phenol 6052-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578 222° C.yloxy)methyl]-4-(2-fluoroethoxy)phenol 6062-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578 114° C.yloxy)methyl]-4-(3-fluoropropoxy)phenol 6072-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 272A, 561B 111° C.yloxy)methyl]-4-fluoro-6-methylphenol 6082-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 272A, 561B 132° C.yloxy)methyl]-6-fluoro-4-methoxyphenol 6092-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578 140° C.yloxy)methyl]-4-phenoxyphenol 6102-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578 108° C.yloxy)methyl]-4-fluoro-6-methoxyphenol 6112-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578 139° C.yloxy)methyl]-4,5-dimethylphenol 6122-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578 128° C.yloxy)methyl]-4-(3-fluoropropylsulfanyl)phenol 6132-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 1A, 561B 102° C.yloxy)methyl]-4-fluoro-5-methylphenol 6142-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578 127° C.yloxy)methyl]-4-(2-fluoroethylsulfanyl)phenol 6153-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578 129° C.yloxy)methyl]-2-hydroxybiphenyl 6162-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578 105° C.yloxy)methyl]-6-ethylphenol 6172-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 272A, 561B 144° C.yloxy)methyl]-5-trifluoromethylphenol 6182-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 1A, 561B 189° C.yloxy)methyl]-4-hydroxyphenol 6192-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578 125° C.yloxy)methyl]-5,6,7,8-tetrahydro-1-naphthol 6202-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578 126° C.yloxy)methyl]-6-trifluoromethoxyphenol 6212-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578 133° C.yloxy)methyl]-5-trifluoromethoxyphenol 6226-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578 163° C.yloxy)methyl]-2-fluoro-3,4-dimethylphenol 6236-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578  97° C.yloxy)methyl]-3-fluoro-2-methylphenol 6246-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578 146° C.yloxy)methyl]-2,4-difluoro-3-methylphenol 6256-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 578 184° C.yloxy)methyl]-2,3-difluorophenol

Further examples can be prepared according to the described generalmethods:

General Example Product methods TLC 450(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4- 165C, 249, 0.22(A)yloxy)methyl]phenyl}-azetidin-3- 423B yl)dimethylamine, oxalate 4521-{3-[(1H-benzimidazol-2-yl)(1- 423B 0.18(D) methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ol, oxalate 4612-{(1-methylpiperidin-4-yloxy)[3-(pyrrolidin-3- 272A, 272B, 0.04(D)yloxy)phenyl]methyl}-1H-benzimidazole, 258 dioxalate 4962-[(5-chloro-2-fluorophenyl)(1- 272A, 272B 0.14(B)methylpiperidin-4-yloxy)methyl]-1H- benzimidazole, oxalate 4982-[(2-fluoro-5-trifluoromethylphenyl)(1- 272A, 272B 0.25(A)methylpiperidin-4-yloxy)methyl]-1H- benzimidazole, oxalate 5036-{3-[(1-ethyl-1H-benzimidazol-2-yl)(1- 194, 189, 0.08(E)methylpiperidin-4-yloxy)methyl]phenyl}hex-5- 472 ynylamine, oxalate 5042-[(2-fluoro-5-methoxyphenyl)(1- 165C, 449A 0.33(E)methylpyrrolidin-3-ylmethoxy)methyl]-1H- benzimidazole, oxalate 5172-[(1-methylpiperidin-4-yloxy)(3- 272A, 272B 0.36(A)trifluoromethylsulfanylphenyl)methyl]-1H- benzimidazole, oxalate 5182-[(4-fluoro-3-trifluoromethoxyphenyl)(1- 272A, 272B 0.32(A)methylpiperidin-4-yloxy)methyl]-1H- benzimidazole, oxalate 5192-[(2-fluoro-5-propoxyphenyl)(1- 272A, 272B 0.33(A)methylpiperidin-4-yloxy)methyl]-1H- benzimidazole, oxalate 5974-[(1H-benzimidazol-2-yl)(1-methylpiperidin- 578 0.20(A)4-yloxy)methyl]phenol Eluent A: CH₂Cl₂/MeOH/NH₄OH 90/10/0.5 Eluent B:CH₂Cl₂/MeOH/NH₄OH 95/5/0.5 Eluent C: CH₂Cl₂/MeOH 90/10 Eluent D:CH₂Cl₂/MeOH/NH₄OH 90/10/1 Eluent E: CH₂Cl₂/MeOH/NH₄OH 80/20/0.5

Further examples can be prepared according to the described generalmethods:

General Example Product methods 4912-{[3-(3,3-difluoropyrrolidin-1-yl)phenyl](1-methylpiperidin-4- 272A,yloxy)methyl}-1H-benzimidazole, dioxalate 272B ¹H NMR of the base(CDCl₃): 9.90 (sl, 1H), 7.69 (sl, 1H), 7.18 (m, 3H), 6.86 (d, 1H), 6.64(s, 1H), 6.43 (d, 1H), 5.80 (s, 1H), 3.65-3.35 (m, 5H), 2.67 (m, 2H),2.38 (m, 3H), 2.22 (s, 3H), 2.20-1.60 (m, 5H) 4922-{[3-(5-fluorohexahydrocyclopenta[c]pyrrol-2-yl)phenyl](1- 423Bmethylpiperidin-4-yloxy)methyl}benzothiazole, dioxalate ¹H NMR of thebase (CDCl₃): 7.96 (d, 1H), 7.85 (d, 1H), 7.15-7.50 (m, 3H), 6.90 (d,1H), 6.80 (s, 1H), 6.57 (d, 1H), 5.85 (s, 1H), 5.25 (d, 1H), 3.66 (m,1H), 3.33 (m, 2H), 3.17 (m, 2H), 3.00 (m, 2H), 2.73 (m, 2H), 2.30 (s,3H), 2.40-1.60 (m, 10H). 4516-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 432, 150yloxy)methyl]phenylsulfanyl}hexylamine, oxalate ¹H NMR (base): 7.65-7.48(m, 2H), 7.43 (s, 1H), 7.30-7.15 (m, 5H), 5.85 (s, 1H), 3.60-3.45 (m,1H), 2.86 (t, 2H, J = 7.1 Hz), 2.78-2.60 (m, 4H), 2.23 (s, 3H),2.18-1.50 (m, 10H), 1.50-1.20 (m, 2H). 4575-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 359Byloxy)methyl]phenylsulfanylmethyl}oxazolidin-2-one mp = 109° C. 458N-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 278, 432,yloxy)methyl]phenylsulfanyl}hexyl)guanidine, dihydrochloride 150 ¹H NMR(dmso-d₆): 7.65-7.48 (m, 2H), 7.43 (s, 1H), 7.30-7.15 (m, 5H), 5.85 (s,1H), 3.60-3.45 (m, 1H), 2.86 (t, 2H, J = 7.1 Hz), 2.78-2.60 ‘m, 4H),2.23 (m, 3H), 2.18-1.50 (m, 10H), 1.50-1.20 (m, 2H). 4734-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 437B,yloxy)methyl]phenylsulfanyl}but-2-enylamine 359B, MS, [M = H]⁺ = 423.2474 4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 437B,yloxy)methyl]phenylsulfanyl}but-2-enylamine, oxalate 359B, 478N-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 401yloxy)methyl]phenylsulfanyl}ethyl)-N-isobutyrylguanidine MS, [M + H]⁺ =509.2; [M + Na]⁺ = 531.1 4883-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 437B, 53yloxy)methyl]phenyl}allylamine mp = 183° C.; MS, [M + H]⁺ = 377.3; [M +Na]⁺ = 399.1 494 cis-2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-437B, yloxy)methyl]phenylsulfanylmethyl}cyclopropylmethylamine 359B mp =99° C.; MS, [M + H]⁺ = 437.1; [M + Na]⁺ = 459.2 499N-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4- 278,yloxy)methyl]phenyl}allyl)guanidine, trihydrochloride 437B, 359B MS,[M + H]⁺ = 419.2; [M + Na]⁺ = 441.3 5022-[(azetidin-3-ylmethoxy)(3-bromophenyl)methyl]-1H-benzimidazole 210,165D, E mp = 104° C. 5062-[(3-bromophenyl)(1-methylazetidin-3-ylmethoxy)methyl]-1H- 165C,benzimidazole 437B, 210, 165D, E MS, ⁷⁹Br [M + H]⁺ = 386.1; [M + Na]⁺ =408.0; MS, ⁸⁰Br [M + H]⁺ = 388.0; [M + Na]⁺ = 410.0 5122-[(2,6-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H- 272A, 1Bbenzimidazole mp = 210° C. 5132-[(2-fluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H- 272A,1B benzimidazole mp = 85° C. 5142-[(5-ethylsulfanyl-2-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-150, 272A, 1H-benzimidazole 1B mp = 90° C. 5152-[(azetidin-3-ylmethoxy)(2-fluoro-5-trifluoromethoxyphenyl)methyl]-165B, A, 1H-benzimidazole, oxalate D, E ¹H NMR (base): 7.57-7.62 (m,2H), 7.38-7.52 (m, 1H), 7.25-7.11 (m, 4H), 6.07 (s, 1H), 3.99-3.90 (m,2H), 3.80-3.74 (m, 2H), 3.64-3.51 (m, 2H), 2.88-3.00 (m, 1H). 5162-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylazetidin-3- 165C, B,ylmethoxy)methyl]-1H-benzimidazole, oxalate A, D, E ¹H NMR (base):7.65-7.48 (m, 2H), 7.38-7.33 (m, 1H), 7.25-7.10 (m, 4H), 6.04 (s, 1H),3.89-3.70 (m, 2H), 3.44-3.48 (m, 1H), 3.32-3.38 (m, 3H), 2.52-2.76 (m,1H), 2.44 (m, 3H) 5202-[(3-ethylsulfanyl-2,6-difluorophenyl)(1-methylpiperidin-4- 150, 272A,yloxy)methyl]-1H-benzimidazole 1B mp = 150° C. 5212-[(2,2-difluorobenzo[1,3]dioxol-5-yl)(1-methylpiperidin-4- 272A, 1Byloxy)methyl]-1H-benzimidazole MS, [M + H]⁺ = 402.1 5382-[(piperidin-4-yloxy)thiophen-3-ylmethyl]-1H-benzimidazole 165B, A, D,E ¹H NMR: 9.50 (sl, 1H), 7.75 (sl, 1H), 7.48 (sl, 1H), 7.38-7.22 (m,5H), 7.12-7.05 (m, 1H), 5.98 (s, 1H), 3.75-3.60 (m, 1H), 3.20-3.05 (m,2H), 2.72-2.55 (m, 2H), 2.10-1.85 (m, 2H), 1.70-1.45 (m, 2H) 5392-[(1-methylpiperidin-4-yloxy)thiophen-3-ylmethyl]-1H-benzimidazole165C, B, A, D, E MS, [M + H]⁺ = 328.03 5442-[(piperidin-4-yloxy)thiophen-2-ylmethyl]-1H-benzimidazole 165B, A, D,E mp = 185° C. 5462-[(1-methylpiperidin-4-yloxy)thiophen-2-ylmethyl]-1H-benzimidazole165C, B, A, D, E mp = 85° C.

Preparation of Starting Materials

Salicaldehydes can be prepared from the corresponding phenols accordingto following procedures (non exhaustive):

-   -   with paraformaldehyde, magnesium chloride and triethylamine        according J. Med. Chem., 2006, 49 (26), pp 7731-7739.    -   protection of phenol with a tetrahydropyranyl (THP) group        followed by metalation and addition of dimethylformamide and        final THP deprotection according to WO2009/089057    -   with the Reimer-Tiemann procedure Org. React. 1982, 28, 2)    -   with hexamethylenetetramine (Duff reaction, Organic Syntheses        Coll. Vol. 10, p. 96; Vol. 75, p. 1)

Biological Data

In Vitro Evaluation of Compounds

Membrane Preparation

SH-SY5Y cells stably expressing human H4 receptor are grown untilsub-confluence and centrifuged at 300 g 15 minutes at 4° C. Pellets areresuspended in buffer I Tris-HCl 50 mM, MgCl₂ 10 mM, NaCl 140 mM, pH=7.4supplemented by Leupeptin 10 μg/mL, Phenyl Methyl Sulphonyl Fluoride(PMSF) 0.1 mM, Aprotinin 2 μg/mL and Pepstatin 2 μM (or a 1/50 dilutionof a mix of protease inhibitors). The obtained suspension is stirredgently and submitted to a 25-26×g mechanic pressure exerted through asyringe. The cell lysate is then centrifuged at 300 g 15 minutes at 4°C. in order to eliminate nucleus and cell scraps. The obtainedsupernatant is then centrifuged at 48000 g for 30 minutes at 4° C. Thefinal pellet is resuspended in buffer I with a potter homogenizer.Aliquots are frozen in liquid nitrogen and stored until use at −80° C.Protein content is measured by the Bradford method.

GTPγ [³⁵S] Binding

Defreezed membranes are diluted at a final concentration of 5 μg/180μL/well in buffer I supplemented by GDP 10 μM and distributed in 96 wellpolystyrene microplate. GTPγ [³⁵S] labelled ligand (0.2-0.3 nM) is addedfor additional 30 minutes. After transfer in a Millipore GF/C HTS®microplate, the filtration of the reactional mix is followed by a threetimes 250 μl wash to stop the reaction.

The filter-bound radioactivity is measured in a liquid scintillationcounter Microbeta TRILUX® with 50 μl of scintillation fluid.

GTPγ [³⁵S] dependent binding activity is determined in vitro forHistamine, Imetit, R(−)-alpha-methyl-histamine and all our compounds.

Compounds can also be tested against Histamine or Imetit to evaluatetheir antagonist potential. Results are expressed with IC50 and Kivalues.

Membrane Preparation

CHO cells stably expressing human H4 receptor were grown untilsub-confluence and centrifuged at 300 g 15 minutes at 4° C. Pellets wereresuspended in buffer I Tris-HCl 50 mM, MgCl₂ 10 mM, NaCl 140 mM, pH=7.4supplemented by a 1/50 dilution of a mix of protease inhibitors. Theobtained suspension is stirred gently and submitted to a 25-26×gmechanic pressure exerted through a syringe. The cell lysate is thencentrifuged at 300 g 15 minutes at 4° C. in order to eliminate nucleusand cell scraps. The obtained supernatant was then centrifuged at 48000g for 30 minutes at 4° C. The final pellet is resuspended in buffer Iwith a potter homogenizer. Aliquots were frozen in liquid nitrogen andstored until use at −80° C. Protein content is measured by the Bradfordmethod.

[³H]Histamine Binding

Defreezed membranes were diluted at a final concentration of 20 μg/180μL/well in a binding buffer containing 50 mM Tris/HCl, 0.5 mM EDTA,pH=7.4 and distributed in 96 well polystyrene microplate. [³H] Histaminelabelled ligand (10-15 nM) is added for 60 minutes with compounds atroom temperature under continuous stirring. Non specific binding wasestimated in the presence of 10 μM BP1.2404 (JNJ 7777120). The reactionwas terminated by filtration through GF/B filters pre-soaked 2 hours at4° C. in 1% polyethyleneimine. Filters were rinsed 3 times with 250 μlof ice cold incubation binding buffer.

The filter-bound radioactivity was measured in a liquid scintillationcounter Microbeta TRILUX® with 50 μl of scintillation fluid.

The hH4 binding investigated by use of [³H] Histamine give a Bmax ˜1pmole/mg prot and a Kd ˜9 nM.

Racemates described hereabove have been evaluated in the GTPγ [³⁵S]assay or in the [³H] histamine binding assay and have been found activewith a Ki or IC50 under 1000 nM.

Example Activity 1 B 2 A 3 B 4 A 5 B 6 B 7 B 8 C 9 C 10 C 11 C 12 B 13 B14 A 15 B 16 C 17 A 18 B 19 B 20 B 21 B 22 C 23 C 24 A 25 C 26 C 27 C 28B 29 A 30 B 31 C 32 B 33 B 34 B 35 A 36 B 37 A 38 B 39 B 40 C 41 C 42 C43 B 44 A 45 C 46 B 47 C 48 B 49 A 50 C 51 C 52 A 53 B 54 B 55 C 56 B 57C 58 B 59 C 60 C 61 C 62 C 63 B 64 A 65 C 66 A 67 C 68 B 69 C 70 B 71 B73 B 74 B 75 C 76 B 77 B 78 B 79 B 80 B 81 B 82 B 83 B 84 A 85 B 86 B 87B 88 C 89 B 90 B 91 C 92 B 93 B 94 C 95 C 96 B 97 B 98 B 99 B 100 B 101C 102 C 103 B 104 C 105 C 106 B 107 C 108 B 109 B 110 B 111 C 112 A 113C 114 B 115 B 116 B 117 C 118 C 119 B 120 A 121 B 122 B 123 A 124 C 125C 126 B 127 B 128 B 129 C 130 B 131 B 132 B 133 B 134 B 135 B 136 B 137B 138 B 139 C 140 B 141 B 142 B 143 B 144 C 145 B 146 B 147 B 148 B 149C 150 B 151 B 152 C 153 C 154 B 155 B 156 C 157 B 158 C 159 C 160 C 161C 162 C 163 C 164 B 165 B 166 C 167 C 168 B 169 A 170 B 171 C 172 B 173B 174 B 175 B 176 C 177 B 178 B 179 B 180 C 181 C 182 C 183 B 184 B 185C 186 A 187 C 188 C 189 B 190 B 191 B 192 B 193 B 194 B 195 B 196 C 197C 198 C 199 B 200 B 201 C 202 C 203 A 204 B 205 A 206 B 207 A 208 B 209B 210 A 211 B 212 A 213 B 214 B 215 B 216 B 217 B 218 C 219 A 220 C 221B 222 B 223 B 224 B 225 B 226 B 227 C 228 C 229 C 231 B 232 A 233 B 234B 235 A 236 B 237 B 238 A 239 A 240 B 241 B 242 A 243 B 244 B 245 B 246B 247 B 248 B 249 B 250 B 251 A 252 A 253 C 254 C 255 C 256 C 257 A 258B 259 B 260 C 261 B 262 B 263 A 264 B 265 B 266 B 267 C 268 B 269 C 270A 271 C 272 A 273 A 274 B 275 B 276 C 277 B 278 C 279 A 280 B 281 A 282A 283 C 284 B 285 A 286 B 287 C 288 A 289 C 290 B 291 B 292 B 293 B 294C 295 B 296 B 297 B 298 A 299 A 300 B 301 C 302 C 303 B 304 C 305 C 306B 307 A 308 B 309 B 310 B 311 B 312 B 313 B 314 C 315 A 316 B 317 A 318C 319 C 320 C 321 C 322 A 323 A 324 B 325 C 326 C 327 B 328 C 330 B 331B 332 A 333 B 334 B 335 B 336 B 337 C 338 B 339 B 340 C 341 B 342 B 343B 344 B 345 B 346 B 347 A 348 A 349 B 350 A 351 A 352 B 353 B 354 C 355B 356 A 357 B 358 C 359 C 360 A 361 A 362 A 363 B 364 A 365 B 366 C 367B 368 C 369 A 370 A 371 C 372 C 373 C 374 C 375 A 376 A 377 B 378 A 379A 380 B 381 C 382 C 383 B 384 B 385 B 386 C 387 C 388 A 389 B 390 C 391A 392 A 393 C 394 A 395 B 396 A 397 B 398 B 399 B 400 C 401 B 402 B 403B 404 B 405 B 406 C 407 C 408 B 409 B 410 B 411 A 412 A 413 B 414 B 415B 416 B 417 A 418 C 419 A 421 C 422 C 423 B 424 B 425 C 426 B 427 B 428B 429 B 430 C 431 C 433 C 435 C 436 C 437 C 438 C 439 C 440 C 441 C 442C 443 C 444 B 445 B 446 B 447 A 448 B 449 C 450 A 451 B 452 B 453 C 454C 455 C 456 A 457 C 458 B 459 C 460 A 461 B 462 B 463 A 464 C 465 C 466C 467 C 468 B 469 A 470 B 471 B 472 B 473 C 474 C 475 B 476 C 477 A 478B 479 C 480 B 481 A 482 C 483 B 484 C 485 A 486 C 487 C 488 A 489 C 490B 491 A 492 A 493 C 494 C 495 C 496 B 497 A 498 B 499 C 500 B 501 B 502A 503 B 504 C 505 A 506 B 507 C 508 C 509 C 510 B 511 B 512 C 513 C 514C 515 A 516 B 517 C 518 A 519 C 520 B 521 A 522 C 523 C 524 B 525 B 526C 527 C 528 B 529 B 530 A 531 C 532 B 533 C 534 B 535 B 536 C 537 A 538A 539 B 540 B 541 C 542 C 543 C 544 A 545 B 546 B 547 A 548 C 549 A 550C 551 B 552 B 553 A 554 B 555 C 556 C 557 C 558 C 559 C 560 B 561 C 562C 563 B 564 C 565 B 566 C 567 B 568 C 569 C 570 B 571 C 572 C 573 B 574C 575 C 576 C 577 B 578 C 579 A 580 A 581 C 582 C 583 B 584 C 585 C 586C 587 C 588 C 589 A 590 A 591 B 592 B 593 C 594 C 595 B 596 C 597 A 598B 599 B 600 C 601 C 602 B 603 B 604 B 605 C 606 B 607 A 608 B 609 B 610A 611 C 612 C 613 C 614 C 615 B 616 C 617 C 618 C 619 B 620 C 621 C 622B 623 C 624 C 625 C 627 C A: Ki or IC50 <1000 nM B: Ki or IC50 <300 nMC: Ki or IC50 <30 nM

1. A method for treating and/or preventing a disease associated with H₄dysfunction, said method comprising administering a compound of formula(I) to a patient in need of treatment therefrom to thereby treat and/orprevent a disease associated with H₄ dysfunction, said compound offormula (I) being:

wherein: X represents NR′, S or O; HetAr represents a phenyl orheteroaryl, optionally substituted with one or more substituents chosenfrom halogen, OR″ alkyl, cyano, NR″R′″, —COR″, —COOR″, —CONR″R′″, aryl,-alkylaryl; R represents a lower alkyl or H R′ represents H, loweralkyl, alkoxyalkyl or alkoxycarbonyl; R″, R′″ identical or differentindependently represent H or alkyl; HET representing a non aromaticmonocyclic heterocycle containing at least one nitrogen atom, which islinked to R; B represents a single bond or an -alkyl- group; Arepresents O, NH or S; Ar is a mono or polycyclic aromatic or a mono orpolycyclic heteroaromatic which can be optionally substituted with oneor more of: halo; azido; cyano; hydroxy; nitro; alkyl; alkoxy;alkylsulfanyl; alkenyl; alkynyl; alkenyloxy; alkenyloxy;alkenylsulfanyl; alkynylsulfanyl; cycloalkoxy; cyloalkylalkyl; whosealkyl, alkenyl, alkynyl or cycloalkyl part can be substituted with oneor more of halo, hydroxy, polyhydroxy, alkoxy, hydroxyalkoxy, cyano,amino, aminoalkyl, alkylamino, dialkylamino, aminoalkylamino,aminoalkylaminocarbonyl, alkoxycarbonylamino, diarylmethylimino (wherearyl is optionally substituted with one or more of hydroxy or halo),cycloalkenylimino (where cylalkenyl is optionally substituted with oneor more of alkyl, OH), alkylsulfanyl, alkylsulfinyl, alkylsulfonyl,cycloalkyl, polycycloalkyl, cycloalkenyl, polycycloalkenyl, guanidino,alkylcarbonylguanidino, acylguanidino, cyanoguanidino,alkoxycarbonylguanidino, alkoxycarbonyl, alkoxycarbonylalkylamino,alkoxycarbonylalkylcycloalkyl, alkoxycarbonylheterocyclyl,aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonylalkoxy,aryloxy, arylsulfanyl, arylsulfinyl, arylsulfonyl, heteroaryl,heterocyclyl (heterocyclyl being optionally substituted with one or moreof oxo, amino, imino), heteroaryloxy, heterocyclyloxy, heteroarylamino,heterocyclylamino, hydrazinocarbonyl, hydroxyalkylcycloalkyl,N-alkyl(thioureido), phthalimido, ureido, oxocycloalkenylaminosubstituted with amino, carbamimidoylheterocyclyl; amino; alkylamino;alkylcarbonyl; alkoxycarbonyl; alkylsulfanyl; alkylsulfinyl;alkylsulfonyl; alkylsulfonyloxy whose alkyl can be substituted with oneor more of halo; aminocarbonyl which can be N-substituted with one ortwo of alkyl, aryl, arylalkyl; aryl; arylalkyl; aryloxy; arylalkoxy;arylalkylamino; arylalkylsulfanyl; heteroaryl; heteroaryloxy whose arylpart can be substituted with one or more of amino, halo, alkyl,(poly)haloalkyl, hydroxyalkyl, alkoxy, (poly)haloalkoxy,alkoxycarbonylamino, alkylcarbonyl, alkylsulfanyl, alkylsulfinyl,alkylsulfonyl, nitro, cyanoalkyl, or fused with a non aromaticheterocycle; heterocyclyl; heterocyclyloxy; heterocyclylalkoxy whoseheterocycle can be substituted with one or more of halogenoalkyl,acylamino, acyloxy, amino, alkyl, alkylamino, dialkylamino, aminoalkyl,oxo, carbamimidoyl, halo, hydroxy, hydroxyalkyl, hydroxymethyl,alkoxcarbonyl; or fused with a non aromatic heterocycle (optionallysubstituted with one or more of halogens) or carbocycle; as well astheir enantiomers, diastereomers, mixtures thereof and pharmaceuticallyacceptable salts, tautomers, hydrates and solvates.
 2. The methodaccording to claim 1, wherein the disease is selected from the groupconsisting of: respiratory diseases including respiratory inflammatorydiseases, adult respiratory distress syndrome, acute respiratorydistress syndrome, bronchitis, chronic bronchitis, chronic obstructivepulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, chronicsinusitis, allergy, allergy induced airway responses, allergic rhinitis,viral rhinitis, non-allergic rhinitis, perennial and seasonal rhinitis,conjunctivitis, nasal congestion, allergic congestion; disorders of thegenito-urinary tract including female and male sexual dysfunction,overactive bladder conditions, urinary incontinence, bladderoveractivity, benign prostate hyperplasia and lower urinary tractsymptoms; dermatological diseases including dermatitis and psoriasis andtreatment of itchy skin; diseases of the cardiovascular system includingthromboembolic diseases, atherosclerosis, myocardial infarction, anginapectoris, myocardial ischaemia and arrhythmia, peripheral arterialocclusive diseases, pulmonary embolisms or deep venous thromboses,hypotension, pulmonary hypertension, malignant hypertension, cardiacinsufficiency, heart or kidney failure, stroke and renal dysfunction;diseases of the gastrointestinal tract including inflammatory boweldisease, Crohn's disease, ulcerative colitis, food allergy; autoimmuneand inflammatory diseases including rheumatoid arthritis, multiplesclerosis; cancer; pain; chronic hypereosinophilias; chronic diseasesassociated with mast-cell multiplication; and lymphatic system diseases.3. The method of claim 1, wherein: X represents NR′ or S; HetArrepresents a phenyl, optionally substituted with one or moresubstituents chosen from hydrogen, halogen, amino, alkyl; R represents Hor a lower alkyl; R′ represents H, alkyl, alkoxyalkyl, alkoxycarbonyl;HET representing a non aromatic 5 or 6 membered heterocycle containingone nitrogen atom, which is linked to R; B represents a single bond or a—CH₂— group; A represents O, NH or S; Ar is a thienyl, phenyl or naphtylor 5 to 6 membered heteroaromatic where the phenyl can be optionallysubstituted with one or more of: halo; azido; cyano; hydroxy; nitro;alkyl; alkoxy; alkylsulfanyl; alkenyl; alkenylsulfanyl; alkynyl;alkenyloxy; alkenyloxy; cycloalkoxy; cyloalkylalkyl whose alkyl,alkenyl, alkynyl or cycloalkyl part can be substituted with one or moreof halo, hydroxy, alkoxy, hydroxyalkoxy, cyano, amino, aminoalkyl,alkylamino, aminoalkylamino, dialkylamino, aminoalkylaminocarbonyl,alkoxycarbonylamino, diarylmethylimino (where aryl is optionallysubstituted with one or more of hydroxy or halo), cycloalkenylimino(where cylalkenyl is optionally substituted with one or more of alkyl,OH), alkylsulfanyl, alkylsulfonyl, cycloalkyl, (poly)cycloalkenyl,guanidino, alkylcarbonylguanidino, acylguanidino,alkoxycarbonylguanidino, alkoxycarbonyl, alkoxycarbonylalkylamino,alkoxycarbonylheterocyclyl, aminocarbonyl, alkylaminocarbonyl,alkylcarbonyl, alkylcarbonylalkoxy, aryloxy, arylsulfonyl, heteroaryl,heterocyclyl (heterocyclyl being optionally substituted with one or moreof oxo, amino, imino), heterocyclylamino, hydrazinocarbonyl,N-alkyl(thioureido), phthalimido, ureido, oxocycloalkenylaminosubstituted with amino, carbamimidoylheterocyclyl; amino; alkylamino;alkylcarbonyl; alkoxycarbonyl; alkylsulfanyl; alkylsulfonyl;alkylsulfonyloxy whose alkyl can be substituted with one or more ofhalo; aminocarbonyl which can be N-substituted with one or two of alkyl,aryl, arylalkyl; aryl; arylalkyl; aryloxy; arylalkoxy;arylalkylsulfanyl; heteroaryl; heteroaryloxy whose aryl part can besubstituted with one or more of amino, halo, alkyl, (poly)haloalkyl,hydroxyalkyl, alkoxy, (poly)haloalkoxy, alkoxycarbonylamino,alkylcarbonyl, alkylsulfanyl, nitro, cyanoalkyl, or is fused with a nonaromatic heterocycle; heterocyclyloxy; heterocyclylalkoxy; heterocyclylwhose heterocycle can be substituted with one or more of halo,halogenoalkyl, acylamino, acyloxy, amino, alkyl, alkylamino,dialkylamino, aminoalkyl, oxo, carbamimidoyl, hydroxy, hydroxyalkyl; orfused with a non aromatic heterocycle (optionally substituted with oneor more of halogens) or carbocycle; as well as their enantiomers,diastereomers, mixtures thereof and pharmaceutically acceptable salts,tautomers, hydrates and solvates.
 4. The method of claim 1, wherein Xrepresents NH or S.
 5. The method of claim 1, wherein HetAr is phenyl.6. The method of claim 1, wherein R represents methyl.
 7. The method ofclaim 1, wherein B represents a single bond.
 8. The method of claim 1,wherein Ar is a phenyl which can be optionally substituted with one ormore of: halo; azido; cyano; hydroxy; nitro; alkyl; alkoxy;alkylsulfanyl; alkenyl; alkynyl; alkenyloxy; alkenyloxy; whose alkyl;alkenyl or alkynyl part can be substituted with one or more of halo,hydroxy, alkoxy, hydroxyalkoxy, cyano, amino, alkylamino,aminoalkylamino, alkylsulfanyl, alkylsulfonyl, cycloalkyl,(poly)cycloalkenyl, guanidino, acylguanidino, alkoxycarbonylguanidino,alkoxycarbonyl, alkoxycarbonylalkylamino, alkoxycarbonylheterocyclyl,aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonylalkoxy,aryloxy, arylsulfonyl, heteroaryl, heterocyclyl, heterocyclylamino,hydrazinocarbonyl, N-alkyl(thioureido), phthalimido, ureido,oxocycloalkenylamino substituted with amino, carbamimidoylheterocyclyl;amino; alkylamino; alkylcarbonyl; alkoxycarbonyl; alkylsulfanyl;alkylsulfonyl; alkylsulfonyloxy whose alkyl can be substituted with oneor more of halo; aminocarbonyl which can be N-substituted with one ortwo of alkyl, aryl, arylalkyl; aryl; aryloxy; arylalkoxy;arylalkylsulfanyl; heteroaryl whose aryl part can be substituted withone or more of amino, halo, alkyl, (poly)haloalkyl, hydroxyalkyl,alkoxy, (poly)haloalkoxy, alkoxycarbonylamino, alkylcarbonyl,alkylsulfanyl, nitro, cyanoalkyl, or is fused with a non aromaticheterocycle; heterocyclyloxy; heterocyclylalkoxy whose heterocycle canbe substituted with one or more of acylamino, acyloxy, amino, alkyl,carbamimidoyl, hydroxy, hydroxyalkyl; or fused with a non aromaticheterocycle.
 9. The method of claim 1, wherein the compound of formula(I) is selected from the group consisting of:2-[(1-methylpiperidin-4-yloxy)phenylmethyl]benzothiazole2-[(1-methylpyrrolidin-3-yloxy)phenylmethyl]benzothiazole2-[(4-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(4-chlorophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(3-fluorophenyl)(1-methylpiperidin-4-yloxymethyl]benzothiazole2-[(2-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)-p-tolylmethyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)(m-tolyl)methyl]benzothiazole(benzothiazol-2-yl-phenylmethyl)(1-methylpiperidin-4-yl)amine2-[(2,3-dihydrobenzo[1,4]dioxin-6-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(3-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(2,4-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)thiophen-2-ylmethyl]benzothiazole2-[(4-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(3,5-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)thiophen-3-ylmethyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)naphthalen-1-ylmethyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)naphthalen-2-ylmethyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)(5-methylthiophen-2-yl)methyl]benzothiazole2-[benzo[1,3]dioxol-5-yl(1-methylpiperidin-4-yloxy)methyl]benzothiazole[(benzothiazol-2-yl)(m-tolyl)methyl](1-methylpiperidin-4-yl)amine2-[(3-allyloxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)(3-trifluoromethoxyphenyl)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)(4-trifluoromethoxyphenyl)methyl]benzothiazole[benzothiazol-2-yl(3-methoxyphenyl)methyl](1-methylpiperidin-4-yl)amine2-[(1-methylpiperidin-4-yloxy)(3-propoxy-phenyl)methyl]benzothiazole2-[(3-bromo-phenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)(3-phenoxy-phenyl)methyl]benzothiazole5-methyl-2-[(1-methylpiperidin-4-yloxy)phenylmethyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)phenylmethyl]-1H-benzimidazole2-[(1-methylpiperidin-4-yloxy)(3-trifluoromethylphenyl)methyl]benzothiazole2-[(2,3-dihydrobenzofuran-5-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole5-fluoro-2-[(1-methylpiperidin-4-yloxy)phenylmethyl]benzothiazole2-[(4-fluoro-3-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole[benzothiazol-2-yl(4-fluoro-3-methyl-phenyl)methyl](1-methylpiperidin-4-yl)amine(benzothiazol-2-yl-p-tolylmethyl)(1-methylpiperidin-4-yl)amine[(benzofuran-2-yl)(benzothiazol-2-yl)methyl](1-methylpiperidin-4-yl)amine2-[(3-fluoro-5-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole[(1H-benzimidazol-2-yl)phenylmethyl](1-methylpiperidin-4-yl)amine2-[(3-fluoro-5-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole[benzothiazol-2-yl(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amine[benzothiazol-2-yl(3-fluoro-5-methoxyphenyl)methyl](1-methylpiperidin-4-yl)amine[benzothiazol-2-yl(3-fluoro-5-methylphenyl)methyl](1-methylpiperidin-4-yl)amine2-[(3-benzyloxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[benzofuran-5-yl(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(3-ethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole[benzothiazol-2-yl(3-iodophenyl)methyl](1-methylpiperidin-4-yl)amine2-[(1-methylpiperidin-4-yloxy)(3-propoxyphenyl)methyl]-1H-benzimidazole[(1H-benzimidazol-2-yl)(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amine2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole(benzothiazol-2-ylpyridin-3-ylmethyl)(1-methylpiperidin-4-yl)amine2-[biphenyl-3-yl(1-methylpiperidin-4-yloxy)methyl]benzothiazole{3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxymethyl]biphenyl-3-yl}methanol2-[(3-isopropoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole[benzothiazol-2-yl(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amine[benzothiazol-2-yl(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amine[benzothiazol-2-yl(1H-pyrrol-2-yl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-trifluoromethylphenyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-trifluoromethoxyphenyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-ethylphenyl)methyl](1-methylpiperidin-4-yl)amine3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenol2-[(1-methylpiperidin-4-yloxy)(3-pyridin-3-ylphenyl)methyl]benzothiazole[(1H-benzimidazol-2-yl)(3-bromophenyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-benzyloxyphenyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-isopropylphenyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-isobutoxyphenyl)methyl](1-methylpiperidin-4-yl)amine{(1H-benzimidazol-2-yl)[3-(3-methylbutoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-butoxyphenyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-methoxyphenyl)methyl](1-methylpiperidin-4-yl)aminetrifluoromethanesulfonic acid3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl estertrifluoromethanesulfonic acid3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl ester[(1H-benzimidazol-2-yl)(3-cyclohexylmethoxyphenyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-fluorophenyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-methylsulfanylphenyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-hexylphenyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-isopropoxyphenyl)methyl](1-methylpiperidin-4-yl)amine2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-ylamine2-[(3-butylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[biphenyl-3-yl(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole[benzothiazol-2-yl(3-bromophenyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-ethoxyphenyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(m-tolyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-phenoxyphenyl)methyl](1-methylpiperidin-4-yl)amine{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-yl}methanol3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-ylamine[benzothiazol-2-yl(3-isopropoxyphenyl)methyl](1-methylpiperidin-4-yl)amine2-[(1-methylpiperidin-4-yloxy)(3-pyridin-3-ylphenyl)methyl]-1H-benzimidazole1-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-ylamino)methyl]phenyl}ethanone[benzothiazol-2-yl(3-butoxyphenyl)methyl](1-methylpiperidin-4-yl)amine2-[(3-butoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole[benzothiazol-2-yl(3-cyclohexylmethoxyphenyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)biphenyl-3-ylmethyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-pentyloxyphenyl)methyl](1-methylpiperidin-4-yl)amine2-[(2′-methoxybiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)(3′-nitrobiphenyl-3-yl)methyl]benzothiazole{3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-yl}acetonitrile2-[(3′-methoxybiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(4′-methoxybiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole[benzothiazol-2-yl(3-benzyloxyphenyl)methyl](1-methylpiperidin-4-yl)amine(benzothiazol-2-ylbiphenyl-3-ylmethyl)(1-methylpiperidin-4-yl)amine{(1H-benzimidazol-2-yl)[3-(4-fluorobenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-benzylsulfanylphenyl)methyl](1-methylpiperidin-4-yl)amine{(1H-benzimidazol-2-yl)[3-(3-fluorobenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine{(1H-benzimidazol-2-yl)[3-(2-phenoxyethoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine[benzothiazol-2-yl(3-benzylsulfanylphenyl)methyl](1-methylpiperidin-4-yl)amine1-{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-4-yl}ethanone2-[(3′-fluoro-biphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole1-{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-yl}ethanone[benzothiazol-2-yl(3-methylsulfanylphenyl)methyl](1-methylpiperidin-4-yl)amine[(3-allyloxyphenyl)(1H-benzimidazol-2-yl)methyl](1-methylpiperidin-4-yl)amine{(1H-benzimidazol-2-yl)[3-(2-fluorobenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine2-[(1-methylpiperidin-4-yloxy)(2′-methylsulfanylbiphenyl-3-yl)methyl]-1H-benzimidazole2-[(4′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(1-methylpiperidin-4-yloxy)(3′-methylsulfanylbiphenyl-3-yl)methyl]-1H-benzimidazole2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)(4′-trifluoromethylbiphenyl-3-yl)methyl]-1H-benzimidazole{(1H-benzimidazol-2-yl)[3-(tetrahydropyran-2-yloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine2-[(2′-chlorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(3′,4′-dichlorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-2-yl}methanol{(1H-benzimidazol-2-yl)[3-(4-methoxybenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine{(1H-benzimidazol-2-yl)[3-(3-methoxybenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-ylamino)methyl]phenol{3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]biphenyl-2-yl}methanol2-[(1-methylpiperidin-4-yloxy)(3′-methylsulfanylbiphenyl-3-yl)methyl]benzothiazole{(1H-benzimidazol-2-yl)[3-(2-methylbenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine{(1H-benzimidazol-2-yl)[3-(4-methylbenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-nitrophenyl)methyl](1-methylpiperidin-4-yl)amine[(3-azidophenyl)(1H-benzimidazol-2-yl)methyl](1-methylpiperidin-4-yl)amine2-[(3′,4′-dichlorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole{(1H-benzimidazol-2-yl)[3-(2-ethoxyethoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-pent-4-enyloxyphenyl)methyl](1-methylpiperidin-4-yl)amine2-[(4′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(2′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-4-yl}carbamicacid tert-butyl ester2-[(3′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)(4′-trifluoromethylbiphenyl-3-yl)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)(2′,3′,4′-trifluorobiphenyl-3-yl)methyl]benzothiazole2-[(2′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole{3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]biphenyl-4-yl}carbamicacid tert-butyl ester[(1H-benzimidazol-2-yl)(3-furan-2-ylphenyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-but-3-enyloxyphenyl)methyl](1-methylpiperidin-4-yl)amine{(1H-benzimidazol-2-yl)[3-(4-methylpentyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine2-[(1-methylpiperidin-4-yloxy)(3-pyrazol-1-ylphenyl)methyl]benzothiazole2-[(3-benzylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole{(1H-benzimidazol-2-yl)[3-(2,5-difluoro-benzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine2-[(3-benzylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(2-chlorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(3-ethylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(3-ethylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}aceticacid methyl ester2-[(3-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[[3-(2,5-difluorobenzyloxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanol2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanol2-[(3-ethylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}aceticacid methyl ester2-[[3-(2,3-difluorobenzyloxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole{(1H-benzimidazol-2-yl)[3-(2,3-difluoro-benzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine2-[[3-(2-fluoroethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)(m-tolyl)methyl]-1H-benzimidazole5,6-dichloro-2-[(1-methylpiperidin-4-yloxy)phenyl-methyl]-1H-benzimidazole5-fluoro-2-[(1-methylpiperidin-4-yloxy)phenyl-methyl]-1H-benzimidazole2-[(2-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(1-methylpiperidin-4-yloxy)(3-pent-4-enyloxy-phenyl)methyl]benzothiazole2-{(1-methylpiperidin-4-yloxy)[3-(4,4,4-trifluoro-butoxy)phenyl]methyl}benzothiazole5-bromo-2-[(1-methylpiperidin-4-yloxy)phenyl-methyl]-1H-benzimidazole2-[[3-(3-fluorobenzyloxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzonitrile2-[[3-(furan-2-ylmethylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole((1H-benzimidazol-2-yl)-{3-[3-(2-methyl-[1,3]dioxolan-2-yl)-propoxy]phenyl}methyl)(1-methylpiperidin-4-yl)amine{(1H-benzimidazol-2-yl)[3-(4,4,4-trifluoro-butoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine2-[[3-(3-fluoropropoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)-p-tolyl-methyl]-1H-benzimidazole2-{(1-methylpiperidin-4-yloxy)[3-(3,3,3-trifluoro-propoxy)phenyl]methyl}benzothiazole2-[(4-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole{(1H-benzimidazol-2-yl)[3-(2-fluoro-ethoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine((1H-benzimidazol-2-yl)-{3-[2-(6,6-dimethyl-bicyclo[3.1.1]hept-2-en-2-yl)ethoxy]phenyl}methyl)(1-methylpiperidin-4-yl)amine2-[(1-methylpiperidin-4-yloxy)(4′-trifluoromethoxy-biphenyl-3-yl)methyl]-1H-benzimidazole2-[(4′-methoxybiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(3-benzo[1,3]dioxol-5-ylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2[[3-(3-methoxybenzyloxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentan-2-one2-{(1-methylpiperidin-4-yloxy)[3-(3-trifluoromethyl-benzyloxy)phenyl]methyl}benzothiazole4-[benzothiazol-2-yl(3-bromo-phenyl)methoxy]-1,1-dimethylpiperidinium2-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)isoindole-1,3-dione3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-yn-1-ol4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-yn-1-ol5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-yn-1-ol2-[(1-methylpiperidin-4-yloxy)-o-tolyl-methyl]-1H-benzimidazole3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynylamine2-[(3-ethynylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-{(1-methylpiperidin-4-yloxy)[3-(3-nitro-benzyloxy)phenyl]methyl}benzothiazole3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]benzonitrile2-{(1-methylpiperidin-4-yloxy)[3-(1H-[1,2,3]triazol-4-yl)phenyl]methyl}-1H-benzimidazole3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]benzoic acidmethyl ester2-[(1-methylpiperidin-4-yloxy)phenyl-methyl]-3H-benzimidazol-4-ylamine2-[(1-methylpiperidin-4-yloxy)(3-methylsulfanyl-phenyl)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)(3-methylsulfanyl-phenyl)methyl]-1H-benzimidazole2-[(3-methanesulfonylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(4-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}acrylicacid tert-butyl ester3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]benzoic acid ethylester{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}methanol3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}propionicacid tert-butyl ester2[[3-(2-benzenesulfonylvinyl)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)phenyl-methyl]-3H-benzimidazol-4-ol[benzothiazol-2-yl(4′-methoxy-biphenyl-3-yl)methyl](1-methylpiperidin-4-yl)amine2[[3-(2-methanesulfonylvinyl)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(2-chloro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrimidin-2-ol2-[(3-tert-butylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(1-methylpiperidin-4-yloxy)(3-pyrimidin-5-yl-phenyl)methyl]benzothiazole3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}acrylonitrile2-[(1-methylpiperidin-4-yloxy)(3-vinyl-phenyl)methyl]benzothiazole3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]-N-benzyl-N-methylbenzamide3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]-N-propylbenzamide2-[(2,4-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole[(1H-benzimidazol-2-yl)(4′-methoxy-biphenyl-3-yl)methyl](1-methylpiperidin-4-yl)amine3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]-N-methyl-N-phenylbenzamide3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylamine2-[(3-chlorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(4-chlorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-yn-1-ol3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxymethyl}-phenylamine2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanol2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanol2-[(3-azidophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-{(1-methylpiperidin-4-yloxy)[3-(2-pyrazin-2-yl-ethylsulfanyl)phenyl]methyl}-1H-benzimidazole2-{(1-methylpiperidin-4-yloxy)[3-(2-pyrazin-2-yl-ethylsulfanyl)phenyl]methyl}benzothiazole{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}benzyl-amine3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-3-methyl-butan-1-ol4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-yn-1-ol5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-yn-1-ol4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}butan-1-ol(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}-cyclopropyl)aceticacid methyl ester2-{(1-methylpiperidin-4-yloxy)[3-(2-[1,2,3]triazol-2-yl-ethylsulfanyl)phenyl]methyl}benzothiazole2-{(1-methylpiperidin-4-yloxy)[3-(2-[1,2,3]triazol-1-yl-ethylsulfanyl)phenyl]methyl}benzothiazole3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-3-methyl-butan-1-ol2-[(1-methylpiperidin-4-yloxy)(3-morpholin-4-yl-phenyl)methyl]benzothiazole2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethanol2-[(1-methylpiperidin-4-yloxy)(3-vinyl-phenyl)methyl]-1H-benzimidazole3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propan-1-ol1-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propan-2-ol4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butan-1-ol2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine2-{(1-methylpiperidin-4-yloxy)[3-(2-methylsulfanyl-ethoxy)phenyl]methyl}benzothiazole2-[(1-methylpiperidin-4-yloxy)(2-trifluoromethoxy-phenyl)methyl]-1H-benzimidazole2-[(1-methylpiperidin-4-yloxy)-p-tolylmethyl]-1H-benzimidazole2-[(1-methylpiperidin-4-yloxy)-p-tolyl-methyl]-1H-benzimidazole3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propan-1-ol1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propan-2-ol4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butan-1-ol2-(1-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}-cyclopropyl)ethanol3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}propan-1-ol2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-N-methylacetamide2-{(1-methylpiperidin-4-yloxy)[3-(2H-pyrazol-3-yl)phenyl]methyl}benzothiazole2-[(3-bromo-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(2-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetamide{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}aceticacid hydrazide2-{(1-methylpiperidin-4-yloxy)[3-(pyridin-4-ylmethoxy)phenyl]methyl}benzothiazole4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}butan-1-ol2[[3-(furan-2-ylmethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole2-(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}-cyclopropyl)ethanol2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]benzyloxy}propan-2-one2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethylamine2-[(1-methylpyrrolidin-3-yloxy)phenyl-methyl]-1H-benzimidazole[(1H-benzimidazol-2-yl)-p-tolyl-methyl](1-methylpiperidin-4-yl)amine2-[(3-ethylsulfanyl-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole1-(3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyloxy)-propan-2-one1-(3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyloxy)-propan-2-ol2[[3-(2-methoxyethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazoleN-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethyl)methyl-amine2-[(1-methylpiperidin-4-yloxy)(3-trifluoromethoxy-phenyl)methyl]-1H-benzimidazole2-[(2-chlorophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynylamine2-{(1-methylpiperidin-4-yloxy)[3-(pyridin-2-ylmethoxy)phenyl]methyl}benzothiazole2-{(1-methylpiperidin-4-yloxy)[3-(pyridin-3-ylmethoxy)phenyl]methyl}benzothiazole2-[(3-Cyclohexylmethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynylamine5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propane-1,2-diol5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pentylamine2-{3-[benzothiazol-2-yl(1-ethyl-piperidin-4-yloxy)methyl]phenoxy}ethylamine2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethylamine6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}hexan-1-ol4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}butylamine5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}hexan-1-ol3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynylamine2-[benzo[1,3]dioxol-5-yl(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)-urea(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)(4,5-dihydro-thiazol-2-yl)amine2-[(2,3-dihydrobenzo[1,4]dioxin-6-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}butylamineN-(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}propylamineN-tert-butoxycarbonyl-N′-(2-{3-[(benzothiazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}pentylamine2[{3-[2-(1-methyl-1H-imidazol4-yl)ethyl]phenyl}(1-methylpiperidin-4-yloxy)methyl]benzothiazoleN-tert-butoxycarbonyl-N′-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynyl)guanidineN-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}butyl)guanidineN-tert-butoxycarbonyl-N′-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}butyl)guanidine2-{(1-methylpiperidin-4-yloxy)[3-(pyridin-2-ylmethoxy)phenyl]methyl}-1H-benzimidazole3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}propylamine5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pentylamineN-tert-butoxycarbonyl-N′-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}propyl)guanidine3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propylamine2-{(1-methylpiperidin-4-yloxy)[3-(4-[1,2,3]triazol-2-yl-butoxy)phenyl]methyl}benzothiazole2-{(1-methylpiperidin-4-yloxy)[3-(4-[1,2,4]triazol-1-yl-butoxy)phenyl]methyl}benzothiazole(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)(4,5-dihydro-1H-imidazol-2-yl)amineN-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)-N′-cyanoguanidine6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynylamineN-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}propyl)guanidineN-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}propyl)guanidine2-{(1-methylpiperidin-4-yloxy)[3-(4-morpholin-4-yl-butoxy)phenyl]methyl}benzothiazole(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-2-yl)methanol(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-2-yl)methanol6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}hexylamine4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butylamine3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}propylamine4-(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethyl)piperazine-1-carboxylicacid tert-butyl ester4-(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethyl)piperazine-1-carboxylicacid tert-butyl ester2-{(1-methylpiperidin-4-yloxy)[3-(2-piperazin-1-yl-ethoxy)phenyl]methyl}benzothiazole4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}butylamine2-{(1-methylpiperidin-4-yloxy)[3-(4-morpholin-4-yl-butoxy)phenyl]methyl}-1H-benzimidazole2-{(1-methylpiperidin-4-yloxy)[3-(4-piperidin-1-yl-butoxy)phenyl]methyl}-1H-benzimidazole2-[(2-fluoro-3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazoleN-tert-butoxycarbonyl-N′-(-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pentyl)guanidineN-tert-butoxycarbonyl-N′-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)guanidine6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynylamine2-{(1-methylpiperidin-4-yloxy)[3-(1,2,3,6-tetrahydro-pyridin-4-yl)phenyl]methyl}-1H-benzimidazoleN-tert-butoxycarbonyl-N′-(5-{3-[(benzothiazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-5-ynyl)guanidineN-(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)guanidineN-tert-butoxycarbonyl-N′-(6-{3-[(benzothiazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)guanidineN-(6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)guanidine4-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}butyl)piperazine-1-carboxylicacid tert-butyl ester6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hexylamineN-tert-butoxycarbonyl-N′-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)guanidineN-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)guanidine1-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)-3-isopropyl-thiourea2-{(1-methylpiperidin-4-yloxy)[3-(3-[1,2,4]triazol-1-yl-propoxy)phenyl]methyl}benzothiazole2-{(1-methylpiperidin-4-yloxy)[3-(3-[1,2,3]triazol-2-yl-propoxy)phenyl]methyl}benzothiazole2-{(1-methylpiperidin-4-yloxy)[3-(3-morpholin-4-yl-propoxy)phenyl]methyl}benzothiazole4-(3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}propyl)piperazine-1-carboxylicacid tert-butyl ester2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-phenylsulfanyl}ethylamine4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}-3,6-dihydro-2H-pyridine-1-carboxamidine2[[3-(2-chloroethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazoleN-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hexyl)guanidine2-{(1-methylpiperidin-4-yloxy)[3-(2-piperidin-1-yl-ethoxy)phenyl]methyl}-1H-benzimidazoleN-tert-butoxycarbonyl-N′-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)guanidineN-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)guanidine4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butylamine4-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}propyl)piperazine-1-carboxylicacid tert-butyl ester(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethylamino)aceticacid tert-butyl ester4-(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentyl)piperazine-1-carboxylicacid tert-butyl esterN-(6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}hexyl)guanidineN-tert-butoxycarbonyl-N′-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hexyl)guanidineN-(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pentyl)guanidine4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}butylamine[[3-(4-aminobutoxy)phenyl](1H-benzimidazol-2-yl)methyl](1-methylpiperidin-4-yl)amine3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propylamine4-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethyl)piperazine-1-carboxylicacid tert-butyl ester(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethylamino)aceticacid tert-butyl ester5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentylamineN-(4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynyl)guanidineN-(3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)guanidineN-(4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}butyl)guanidine(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentylamino)aceticacid tert-butyl ester2-[(1-methylpiperidin-4-yloxy)(3-piperidin-4-ylethynyl-phenyl)methyl]-1H-benzimidazole2-{(1-methylpiperidin-4-yloxy)[3-(piperidin-4-ylmethoxy)phenyl]methyl}benzothiazole2-{(1-methylpiperidin-4-yloxy)[3-(piperidin-3-ylmethoxy)phenyl]methyl}benzothiazole2[[3-(1-methylpiperidin-3-ylmethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)(3-piperidin-3-ylethynyl-phenyl)methyl]-1H-benzimidazole5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}pentylamine2-{(1-methylpiperidin-4-yloxy)[3-(pyrrolidin-3-yloxy)phenyl]methyl}benzothiazole2-{(1-methylpiperidin-4-yloxy)[3-(pyrrolidin-3-yloxy)phenyl]methyl}benzothiazole5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-en-1-ol3-amino-4-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamino)-cyclobut-3-ene-1,2-dione[[3-(6-aminohex-1-ynyl)phenyl](1H-benzimidazol-2-yl)methyl](1-methylpiperidin-4-yl)amine{[3-(4-aminobutoxy)phenyl]benzothiazol-2-yl-methyl}(1-methylpiperidin-4-yl)amine2-[(3-azetidin-3-ylethynylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-en-1-ol5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-en-1-ol4-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentyl)piperazine-1-carboxylicacid tert-butyl ester2[[3-(2-azetidin-3-ylethyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazoleN-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynyl)guanidine4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}piperidine-1-carboxamidine2-{(1-methylpiperidin-4-yloxy)[3-(2-piperidin-2-yl-ethylsulfanyl)phenyl]methyl}-1H-benzimidazole2-{(1-methylpiperidin-4-yloxy)[3-(2-piperidin-4-yl-ethyl)phenyl]methyl}-1H-benzimidazoleN-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pentyl)guanidine2-[{3-[3-(3H-imidazol-4-yl)propylsulfanyl]phenyl}(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazoleN-tert-butoxycarbonyl-N′-(4-{3-[(benzothiazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynyl)guanidine5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentylamineN-acetyl-N′-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine2[[3-(azetidin-3-yloxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}azetidin-3-ol(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)methanol1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}piperidin-4-ylamine1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ol1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-olN-(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)acetamide2[[3-(5-imidazol-1-ylpent-1-ynyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-{(1-methylpiperidin-4-yloxy)[3-(5-pyrazol-1-yl-pent-1-ynyl)phenyl]methyl}-1H-benzimidazole1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}piperidin-4-ol2-[{3-[2-(1H-imidazol-4-yl)ethyl]phenyl}(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazoleacetic acid1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}piperidin-4-ylester2-[(3-bromo-phenyl)(1-methyl-pyrrolidin-3-ylmethoxy)methyl]-1H-benzimidazole2-{(1-methylpiperidin-4-yloxy)[3-(piperidin-4-yloxy)phenyl]methyl}benzothiazole2-{(1-methylpiperidin-4-yloxy)[3-(5-[1,2,3]triazol-2-yl-pent-1-ynyl)phenyl]methyl}-1H-benzimidazole2-{(1-methylpiperidin-4-yloxy)[3-(5-[1,2,3]triazol-1-yl-pent-1-ynyl)phenyl]methyl}-1H-benzimidazoleN-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)guanidineN1-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentyl)butane-1,4-diamine{[3-(6-aminohex-1-ynyl)phenyl]benzothiazol-2-yl-methyl}(1-methylpiperidin-4-yl)amine5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-enylamine4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}but-2-en-1-ol1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ylamine2-[(2,5-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(2-fluoro-5-iodo-phenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylethynyl}azetidine-1-carboxamidine4-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butan-1-ol2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ylamine2[[3-(3-fluoropyrrolidin-1-yl)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}but-2-enylamine2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole(enantiomer A)2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole(enantiomer B)N-(2-aminoethyl)-2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetamideN-(2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine2-(5-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)isoindole-1,3-dione6-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynylamineoxalate4-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butylamineoxalateN-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propyl)guanidine,dihydrochloride1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-one,oxalateN-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butyl)guanidine,dihydrochloride5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}pentan-1-olN-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)-N-(2,2-dimethylpropionyl)guanidine2-[(1-methylpiperidin-4-yloxy)(4-nitrophenyl)methyl]-1H-benzimidazole2-{(1-methylpiperidin-4-yloxy)[3-(pyridin-3-yloxy)phenyl]methyl}benzothiazole,oxalate2-[(3-bromophenyl)(1-methylpyrrolidin-3-ylmethoxy)methyl]-5-fluoro-1H-benzimidazole,oxalate4-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]aniline4-[(1H-benzimidazol-2-yl)(piperidin-4-yloxy)methyl]aniline,hydrochlorideN-(2-amino-ethyl)-2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetamide1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}-3-trifluoromethylpyrrolidin-3-ol,oxalate2-[[3-(4,5-dihydro-1H-imidazol-2-ylmethylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[[3-(4,5-dihydro-1H-imidazol-2-ylmethylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5,6-difluoro-1H-benzimidazole2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1-methyl-1H-benzimidazole,dioxalate2-amino-5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}-1,5-dihydroimidazol-4-one2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5,6,7-trifluoro-1H-benzimidazole1-(2-ethoxyethyl)-2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,dioxalate3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzaldehyde4-{3-[(1H-benzimidazol-2-yl)(1-methylazetidin-3-ylmethoxy)methyl]phenylsulfanyl}butylamine,oxalate2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzoxazole,oxalate{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}methanol.dimethylsulfoxonium ylide of 3-bromophenylacetic acid methyl ester2-[(2-fluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,enantiomer B2-[(2,6-difluoro-3-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazoleethyl(6-{3-[(1-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)carbamate,oxalate2-[(1H-indol-6-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,oxalate2-[benzo[b]thiophen-6-yl(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,oxalate2-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,enantiomer B2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol2-[(1H-benzimidazol-2-yl)hydroxymethyl]phenol2-[(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylimino)phenylmethyl]phenol5-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylimino)-2-methylcyclopent-1-enol2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,enantiomer B5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine,enantiomer A5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine,enantiomer B2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole,enantiomer A2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole,enantiomer B2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-methylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenolenantiomer A2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenolenantiomer B6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-3-methylphenolenantiomer A6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-3-methylphenolenantiomer B6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2,3-difluorophenolenantiomer A6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2,3-difluorophenolenantiomer B5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}pent-4-ynylamine,dioxalate3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}cyclopentylamine,oxalate2-{[3-(3-fluoropyrrolidin-1-yl)phenyl](1-methylpiperidin-4-yloxy)methyl}benzothiazole,oxalate5-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpyrrolidin-3-ylmethoxy)methyl]phenyl}pent-4-ynylamine,oxalate2-[(3-bromophenyl)(1-methylpyrrolidin-3-ylmethoxy)methyl]benzothiazole,oxalate (one epimer)2-[(3-bromophenyl)(1-methylpyrrolidin-3-ylmethoxy)methyl]benzothiazole,oxalate (50/50 mixture of two epimers)2-{(1-methylpiperidin-4-yloxy)[3-(octahydrocyclopenta[c]pyrrol-5-yloxy)phenyl]methyl}benzothiazole,dioxalate(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)methylamine,dioxalate4-{3-[(5,6-difluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butan-1-ol2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}octahydrocyclopenta[c]pyrrol-5-ylamine,dioxalate2-{[3-(3-fluoropropoxy)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H-benzimidazole,oxalate2-{[3-(2-fluoroethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H-benzimidazole,oxalate4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}cyclohexylamine,oxalate6-{3-[(1-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynylamine,dioxalate1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-2-ylmethylamine,oxalate(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)(methyl)amine,oxalate(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)(dimethyl)amine,oxalate2-{[3-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2-yl)phenyl](1-methylpiperidin-4-yloxy)methyl}benzothiazole,dioxalate2-[(2-fluoro-5-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,oxalate3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenol,oxalate2-{[2-fluoro-5-(2-fluoroethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H-benzimidazole,oxalate2-[(2-fluoro-5-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,oxalate4-{3-[(1-methylpiperidin-4-yloxy)(5,6,7-trifluoro-1H-benzimidazol-2-yl)methyl]phenylsulfanyl}butylamine,oxalate4-{3-[(5,6-difluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butylamine,oxalate6-(3-{[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl](1-methylpiperidin-4-yloxy)methyl}phenyl)hex-5-ynylamine,dioxalate6-(3-{[1-(2-methoxyethyl)-1H-benzimidazol-2-yl](1-methylpiperidin-4-yloxy)methyl}phenyl)hex-5-ynylamine,dioxalate2-{[3-(3-fluoropropylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H-benzimidazole,dioxalate5-fluoro-2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,oxalate4,5,6-trifluoro-2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole5,6-difluoro-2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-{[2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H-benzimidazole2-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(2-chloro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,oxalate2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole,oxalate2-[(4-chloro-2,6-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole7-fluoro-2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,oxalate2-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole,oxalate2-[(4-chloro-2,6-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole,oxalate2-[(3-ethoxy-2,6-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzoxazole,oxalate2-[(1-methylpiperidin-4-yloxy)(4-trifluoromethylphenyl)methyl]-1H-benzimidazole2-[(2-fluoro-4-trifluoromethylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(2,4-dimethylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(3-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[chroman-7-yl(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(2-fluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzoxazole,oxalate2-[(3,5-bis-trifluoromethylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,oxalate5-fluoro-2-[(2-fluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(2,3-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(3-chloro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazoleethyl2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzimidazole-1-carboxylate,oxalate2-[(3-fluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(5-bromo-2-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylamine,oxalate5-{4-fluoro-3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamineethyl(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}pent-4-ynyl)carbamate2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-chlorophenolethyl(5-{4-fluoro-3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)carbamate2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-trifluoromethoxyphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-methoxyphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-methylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-bromophenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-ethoxyphenol2-[(1H-indol-7-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4,6-difluorophenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4,6-dichlorophenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-3-fluorophenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4,5-difluorophenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-fluorophenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-chlorophenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-methylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-methylsulfanylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-ethylsulfanylphenol3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-4-ol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-tert-butylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-propylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-methoxyphenol2-[(1H-benzimidazol-2-yl)(1-methy-piperidin-4-yloxy)methyl]-3-fluoro-5-methylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-3-chlorophenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluoro-4-ethylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-benzylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-trifluoromethylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-chloro-6-fluorophenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-3-methylphenol6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-3-methylphenol6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]indan-5-ol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-propoxyphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-(1-methyl-1-phenylethyl)phenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-(2-fluoroethoxy)phenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-(3-fluoropropoxy)phenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluoro-6-methylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluoro-4-methoxyphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-phenoxyphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluoro-6-methoxyphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4,5-dimethylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-(3-fluoropropylsulfanyl)phenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluoro-5-methylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-(2-fluoroethylsulfanyl)phenol3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-hydroxybiphenyl2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-ethylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-trifluoromethylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-hydroxyphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5,6,7,8-tetrahydro-1-naphthol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-trifluoromethoxyphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-trifluoromethoxyphenol6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-3,4-dimethylphenol6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-3-fluoro-2-methylphenol6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2,4-difluoro-3-methylphenol6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2,3-difluorophenol(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}-azetidin-3-yl)dimethylamine,oxalate1-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ol,oxalate2-{(1-methylpiperidin-4-yloxy)[3-(pyrrolidin-3-yloxy)phenyl]methyl}-1H-benzimidazole,dioxalate2-[(5-chloro-2-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,oxalate2-[(2-fluoro-5-trifluoromethylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,oxalate6-{3-[(1-ethyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynylamine,oxalate2-[(2-fluoro-5-methoxyphenyl)(1-methylpyrrolidin-3-ylmethoxy)methyl]-1H-benzimidazole,oxalate2-[(1-methylpiperidin-4-yloxy)(3-trifluoromethylsulfanylphenyl)methyl]-1H-benzimidazole,oxalate2-[(4-fluoro-3-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,oxalate2-[(2-fluoro-5-propoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,oxalate4-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol2-{[3-(3,3-difluoropyrrolidin-1-yl)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H-benzimidazole,dioxalate2-{[3-(5-fluorohexahydrocyclopenta[c]pyrrol-2-yl)phenyl](1-methylpiperidin-4-yloxy)methyl}benzothiazole,dioxalate6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}hexylamine,oxalate5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}oxazolidin-2-oneN-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}hexyl)guanidine,dihydrochloride4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}but-2-enylamine4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}but-2-enylamine,oxalateN-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)-N-isobutyrylguanidine3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}allylaminecis-2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}cyclopropylmethylamineN-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}allyl)guanidine,trihydrochloride2-[(azetidin-3-ylmethoxy)(3-bromophenyl)methyl]-1H-benzimidazole2-[(3-bromophenyl)(1-methylazetidin-3-ylmethoxy)methyl]-1H-benzimidazole2-[(2,6-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(2-fluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(5-ethylsulfanyl-2-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(azetidin-3-ylmethoxy)(2-fluoro-5-trifluoromethoxyphenyl)methyl]-1H-benzimidazole,oxalate2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylazetidin-3-ylmethoxy)methyl]-1H-benzimidazole,oxalate2-[(3-ethylsulfanyl-2,6-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(2,2-difluorobenzo[1,3]dioxol-5-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(piperidin-4-yloxy)thiophen-3-ylmethyl]-1H-benzimidazole2-[(1-methylpiperidin-4-yloxy)thiophen-3-ylmethyl]-1H-benzimidazole2-[(piperidin-4-yloxy)thiophen-2-ylmethyl]-1H-benzimidazole2-[(1-methylpiperidin-4-yloxy)thiophen-2-ylmethyl]-1H-benzimidazole aswell as their enantiomers, diastereomers, mixtures thereof andpharmaceutically acceptable salts, free forms, tautomers, hydrates andsolvates.
 10. A combination of a compound of formula (I) and one or moretherapeutic agent(s), wherein said compound of formula (I) being:

wherein: X represents NR′, S or O; HetAr represents a phenyl orheteroaryl, optionally substituted with one or more substituents chosenfrom halogen, OR″ alkyl, cyano, NR″R′″, —COR″, —COOR″, —CONR″R′″, aryl,-alkylaryl; R represents a lower alkyl or H R′ represents H, loweralkyl, alkoxyalkyl or alkoxycarbonyl; R″, R′″ identical or differentindependently represent H or alkyl; HET representing a non aromaticmonocyclic heterocycle containing at least one nitrogen atom, which islinked to R; B represents a single bond or an -alkyl- group; Arepresents O, NH or S; Ar is a mono or polycyclic aromatic or a mono orpolycyclic heteroaromatic which can be optionally substituted with oneor more of: halo; azido; cyano; hydroxy; nitro; alkyl; alkoxy;alkylsulfanyl; alkenyl; alkynyl; alkenyloxy; alkenyloxy;alkenylsulfanyl; alkynylsulfanyl; cycloalkoxy; cyloalkylalkyl; whosealkyl, alkenyl, alkynyl or cycloalkyl part can be substituted with oneor more of halo, hydroxy, polyhydroxy, alkoxy, hydroxyalkoxy, cyano,amino, aminoalkyl, alkylamino, dialkylamino, aminoalkylamino,aminoalkylaminocarbonyl, alkoxycarbonylamino, diarylmethylimino (wherearyl is optionally substituted with one or more of hydroxy or halo),cycloalkenylimino (where cylalkenyl is optionally substituted with oneor more of alkyl, OH), alkylsulfanyl, alkylsulfinyl, alkylsulfonyl,cycloalkyl, polycycloalkyl, cycloalkenyl, polycycloalkenyl, guanidino,alkylcarbonylguanidino, acylguanidino, cyanoguanidino,alkoxycarbonylguanidino, alkoxycarbonyl, alkoxycarbonylalkylamino,alkoxycarbonylalkylcycloalkyl, alkoxycarbonylheterocyclyl,aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonylalkoxy,aryloxy, arylsulfanyl, arylsulfinyl, arylsulfonyl, heteroaryl,heterocyclyl (heterocyclyl being optionally substituted with one or moreof oxo, amino, imino), heteroaryloxy, heterocyclyloxy, heteroarylamino,heterocyclylamino, hydrazinocarbonyl, hydroxyalkylcycloalkyl,N-alkyl(thioureido), phthalimido, ureido, oxocycloalkenylaminosubstituted with amino, carbamimidoylheterocyclyl; amino; alkylamino;alkylcarbonyl; alkoxycarbonyl; alkylsulfanyl; alkylsulfinyl;alkylsulfonyl; alkylsulfonyloxy whose alkyl can be substituted with oneor more of halo; aminocarbonyl which can be N-substituted with one ortwo of alkyl, aryl, arylalkyl; aryl; arylalkyl; aryloxy; arylalkoxy;arylalkylamino; arylalkylsulfanyl; heteroaryl; heteroaryloxy whose arylpart can be substituted with one or more of amino, halo, alkyl,(poly)haloalkyl, hydroxyalkyl, alkoxy, (poly)haloalkoxy,alkoxycarbonylamino, alkylcarbonyl, alkylsulfanyl, alkylsulfinyl,alkylsulfonyl, nitro, cyanoalkyl, or fused with a non aromaticheterocycle; heterocyclyl; heterocyclyloxy; heterocyclylalkoxy whoseheterocycle can be substituted with one or more of halogenoalkyl,acylamino, acyloxy, amino, alkyl, alkylamino, dialkylamino, aminoalkyl,oxo, carbamimidoyl, halo, hydroxy, hydroxyalkyl, hydroxymethyl,alkoxcarbonyl; or fused with a non aromatic heterocycle (optionallysubstituted with one or more of halogens) or carbocycle; as well astheir enantiomers, diastereomers, mixtures thereof and pharmaceuticallyacceptable salts, tautomers, hydrates and solvates; and wherein said oneor more therapeutic agent(s) selected from the group consisting of:Histamine H₁, H₂ or H₃ receptor antagonists, Leukotriene antagonists,5-Lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein(FLAP) antagonists CX₁- and α₂-adrenoceptor agonist vasoconstrictorsympathomimetic agents for decongestant use, Xanthines, such astheophylline and aminophylline, Steroidal and non-steroidalantiinflammatories, such as sodium cromoglycate and nedocromil sodium,Ketotifen, COX-1 inhibitors (NSAIDs) and COX-2 selective inhibitors,Immunosuppressants, and mucolytics or anti-tussive agents.
 11. Thecombination according to claim 10, wherein the H₁ receptor antagonist isselected from the group consisting of cetirizine, desloratadine,bepotastine and doxepin.
 12. The combination according to claim 10,wherein: X represents NR′ or S; HetAr represents a phenyl, optionallysubstituted with one or more substituents chosen from hydrogen, halogen,amino, alkyl; R represents H or a lower alkyl; R′ represents H, alkyl,alkoxyalkyl, alkoxycarbonyl; HET representing a non aromatic 5 or 6membered heterocycle containing one nitrogen atom, which is linked to R;B represents a single bond or a —CH₂— group; A represents O, NH or S; Aris a thienyl, phenyl or naphtyl or 5 to 6 membered heteroaromatic wherethe phenyl can be optionally substituted with one or more of: halo;azido; cyano; hydroxy; nitro; alkyl; alkoxy; alkylsulfanyl; alkenyl;alkenylsulfanyl; alkynyl; alkenyloxy; alkenyloxy; cycloalkoxy;cyloalkylalkyl whose alkyl, alkenyl, alkynyl or or cycloalkyl part canbe substituted with one or more of halo, hydroxy, alkoxy, hydroxyalkoxy,cyano, amino, aminoalkyl, alkylamino, aminoalkylamino, dialkylamino,aminoalkylaminocarbonyl, alkoxycarbonylamino, diarylmethylimino (wherearyl is optionally substituted with one or more of hydroxy or halo),cycloalkenylimino (where cylalkenyl is optionally substituted with oneor more of alkyl, OH), alkylsulfanyl, alkylsulfonyl, cycloalkyl,(poly)cycloalkenyl, guanidino, alkylcarbonylguanidino, acylguanidino,alkoxycarbonylguanidino, alkoxycarbonyl, alkoxycarbonylalkylamino,alkoxycarbonylheterocyclyl, aminocarbonyl, alkylaminocarbonyl,alkylcarbonyl, alkylcarbonylalkoxy, aryloxy, arylsulfonyl, heteroaryl,heterocyclyl (heterocyclyl being optionally substituted with one or moreof oxo, amino, imino), heterocyclylamino, hydrazinocarbonyl,N-alkyl(thioureido), phthalimido, ureido, oxocycloalkenylaminosubstituted with amino, carbamimidoylheterocyclyl; amino; alkylamino;alkylcarbonyl; alkoxycarbonyl; alkylsulfanyl; alkylsulfonyl;alkylsulfonyloxy whose alkyl can be substituted with one or more ofhalo; aminocarbonyl which can be N-substituted with one or two of alkyl,aryl, arylalkyl; aryl; arylalkyl; aryloxy; arylalkoxy;arylalkylsulfanyl; heteroaryl; heteroaryloxy whose aryl part can besubstituted with one or more of amino, halo, alkyl, (poly)haloalkyl,hydroxyalkyl, alkoxy, (poly)haloalkoxy, alkoxycarbonylamino,alkylcarbonyl, alkylsulfanyl, nitro, cyanoalkyl, or is fused with a nonaromatic heterocycle; heterocyclyloxy; heterocyclylalkoxy; heterocyclylwhose heterocycle can be substituted with one or more of halo,halogenoalkyl, acylamino, acyloxy, amino, alkyl, alkylamino,dialkylamino, aminoalkyl, oxo, carbamimidoyl, hydroxy, hydroxyalkyl; orfused with a non aromatic heterocycle (optionally substituted with oneor more of halogens) or carbocycle; as well as their enantiomers,diastereomers, mixtures thereof and pharmaceutically acceptable salts,tautomers, hydrates and solvates.
 13. The combination according to claim10, wherein X represents NH or S.
 14. The combination according to claim10, wherein HetAr is phenyl.
 15. The combination according to claim 10,wherein R represents methyl.
 16. The combination according to claim 10,wherein B represents a single bond.
 17. The combination according toclaim 10, wherein Ar is a phenyl which can be optionally substitutedwith one or more of: halo; azido; cyano; hydroxy; nitro; alkyl; alkoxy;alkylsulfanyl; alkenyl; alkynyl; alkenyloxy; alkenyloxy; whose alkyl;alkenyl or alkynyl part can be substituted with one or more of halo,hydroxy, alkoxy, hydroxyalkoxy, cyano, amino, alkylamino,aminoalkylamino, alkylsulfanyl, alkylsulfonyl, cycloalkyl,(poly)cycloalkenyl, guanidino, acylguanidino, alkoxycarbonylguanidino,alkoxycarbonyl, alkoxycarbonylalkylamino, alkoxycarbonylheterocyclyl,aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkylcarbonylalkoxy,aryloxy, arylsulfonyl, heteroaryl, heterocyclyl, heterocyclylamino,hydrazinocarbonyl, N-alkyl(thioureido), phthalimido, ureido,oxocycloalkenylamino substituted with amino, carbamimidoylheterocyclyl;amino; alkylamino; alkylcarbonyl; alkoxycarbonyl; alkylsulfanyl;alkylsulfonyl; alkylsulfonyloxy whose alkyl can be substituted with oneor more of halo; aminocarbonyl which can be N-substituted with one ortwo of alkyl, aryl, arylalkyl; aryl; aryloxy; arylalkoxy;arylalkylsulfanyl; heteroaryl whose aryl part can be substituted withone or more of amino, halo, alkyl, (poly)haloalkyl, hydroxyalkyl,alkoxy, (poly)haloalkoxy, alkoxycarbonylamino, alkylcarbonyl,alkylsulfanyl, nitro, cyanoalkyl, or is fused with a non aromaticheterocycle; heterocyclyloxy; heterocyclylalkoxy whose heterocycle canbe substituted with one or more of acylamino, acyloxy, amino, alkyl,carbamimidoyl, hydroxy, hydroxyalkyl; or fused with a non aromaticheterocycle.
 18. The combination according to claim 10, wherein thecompound of formula (I) is selected from the group consisting of:2-[(1-methylpiperidin-4-yloxy)phenylmethyl]benzothiazole2-[(1-methylpyrrolidin-3-yloxy)phenylmethyl]benzothiazole2-[(4-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(4-chlorophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(3-fluorophenyl)(1-methylpiperidin-4-yloxymethyl]benzothiazole2-[(2-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)-p-tolylmethyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)(m-tolyl)methyl]benzothiazole(benzothiazol-2-yl-phenylmethyl)(1-methylpiperidin-4-yl)amine2-[(2,3-dihydrobenzo[1,4]dioxin-6-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(3-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(2,4-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)thiophen-2-ylmethyl]benzothiazole2-[(4-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(3,5-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)thiophen-3-ylmethyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)naphthalen-1-ylmethyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)naphthalen-2-ylmethyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)(5-methylthiophen-2-yl)methyl]benzothiazole2-[benzo[1,3]dioxol-5-yl(1-methylpiperidin-4-yloxy)methyl]benzothiazole[(benzothiazol-2-yl)(m-tolyl)methyl](1-methylpiperidin-4-yl)amine2-[(3-allyloxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)(3-trifluoromethoxyphenyl)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)(4-trifluoromethoxyphenyl)methyl]benzothiazole[benzothiazol-2-yl(3-methoxyphenyl)methyl](1-methylpiperidin-4-yl)amine2-[(1-methylpiperidin-4-yloxy)(3-propoxy-phenyl)methyl]benzothiazole2-[(3-bromo-phenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)(3-phenoxy-phenyl)methyl]benzothiazole5-methyl-2-[(1-methylpiperidin-4-yloxy)phenylmethyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)phenylmethyl]-1H-benzimidazole2-[(1-methylpiperidin-4-yloxy)(3-trifluoromethylphenyl)methyl]benzothiazole2-[(2,3-dihydrobenzofuran-5-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole5-fluoro-2-[(1-methylpiperidin-4-yloxy)phenylmethyl]benzothiazole2-[(4-fluoro-3-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole[benzothiazol-2-yl(4-fluoro-3-methyl-phenyl)methyl](1-methylpiperidin-4-yl)amine(benzothiazol-2-yl-p-tolylmethyl)(1-methylpiperidin-4-yl)amine[(benzofuran-2-yl)(benzothiazol-2-yl)methyl](1-methylpiperidin-4-yl)amine2-[(3-fluoro-5-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole[(1H-benzimidazol-2-yl)phenylmethyl](1-methylpiperidin-4-yl)amine2-[(3-fluoro-5-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole[benzothiazol-2-yl(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amine[benzothiazol-2-yl(3-fluoro-5-methoxyphenyl)methyl](1-methylpiperidin-4-yl)amine[benzothiazol-2-yl(3-fluoro-5-methylphenyl)methyl](1-methylpiperidin-4-yl)amine2-[(3-benzyloxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[benzofuran-5-yl(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(3-ethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole[benzothiazol-2-yl(3-iodophenyl)methyl](1-methylpiperidin-4-yl)amine2-[(1-methylpiperidin-4-yloxy)(3-propoxyphenyl)methyl]-1H-benzimidazole[(1H-benzimidazol-2-yl)(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amine2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole(benzothiazol-2-ylpyridin-3-ylmethyl)(1-methylpiperidin-4-yl)amine2-[biphenyl-3-yl(1-methylpiperidin-4-yloxy)methyl]benzothiazole{3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxymethyl]biphenyl-3-yl}methanol2-[(3-isopropoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole[benzothiazol-2-yl(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amine[benzothiazol-2-yl(3-propoxyphenyl)methyl](1-methylpiperidin-4-yl)amine[benzothiazol-2-yl(1H-pyrrol-2-yl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-trifluoromethylphenyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-trifluoromethoxyphenyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-ethylphenyl)methyl](1-methylpiperidin-4-yl)amine3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenol2-[(1-methylpiperidin-4-yloxy)(3-pyridin-3-ylphenyl)methyl]benzothiazole[(1H-benzimidazol-2-yl)(3-bromophenyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-benzyloxyphenyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-isopropylphenyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-isobutoxyphenyl)methyl](1-methylpiperidin-4-yl)amine{(1H-benzimidazol-2-yl)[3-(3-methylbutoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-butoxyphenyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-methoxyphenyl)methyl](1-methylpiperidin-4-yl)aminetrifluoromethanesulfonic acid3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl estertrifluoromethanesulfonic acid3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl ester[(1H-benzimidazol-2-yl)(3-cyclohexylmethoxyphenyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-fluorophenyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-methylsulfanylphenyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-hexylphenyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-isopropoxyphenyl)methyl](1-methylpiperidin-4-yl)amine2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-ylamine2-[(3-butylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[biphenyl-3-yl(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole[benzothiazol-2-yl(3-bromophenyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-ethoxyphenyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(m-tolyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-phenoxyphenyl)methyl](1-methylpiperidin-4-yl)amine{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-yl}methanol3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-ylamine[benzothiazol-2-yl(3-isopropoxyphenyl)methyl](1-methylpiperidin-4-yl)amine2-[(1-methylpiperidin-4-yloxy)(3-pyridin-3-ylphenyl)methyl]-1H-benzimidazole1-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-ylamino)methyl]phenyl}ethanone[benzothiazol-2-yl(3-butoxyphenyl)methyl](1-methylpiperidin-4-yl)amine2-[(3-butoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole[benzothiazol-2-yl(3-cyclohexylmethoxyphenyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)biphenyl-3-ylmethyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-pentyloxyphenyl)methyl](1-methylpiperidin-4-yl)amine2-[(2′-methoxybiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)(3′-nitrobiphenyl-3-yl)methyl]benzothiazole{3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-yl}acetonitrile2-[(3′-methoxybiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(4′-methoxybiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole[benzothiazol-2-yl(3-benzyloxyphenyl)methyl](1-methylpiperidin-4-yl)amine(benzothiazol-2-ylbiphenyl-3-ylmethyl)(1-methylpiperidin-4-yl)amine{(1H-benzimidazol-2-yl)[3-(4-fluorobenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-benzylsulfanylphenyl)methyl](1-methylpiperidin-4-yl)amine{(1H-benzimidazol-2-yl)[3-(3-fluorobenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine{(1H-benzimidazol-2-yl)[3-(2-phenoxyethoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine[benzothiazol-2-yl(3-benzylsulfanylphenyl)methyl](1-methylpiperidin-4-yl)amine1-{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-4-yl}ethanone2-[(3′-fluoro-biphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole1-{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-3-yl}ethanone[benzothiazol-2-yl(3-methylsulfanylphenyl)methyl](1-methylpiperidin-4-yl)amine[(3-allyloxyphenyl)(1H-benzimidazol-2-yl)methyl](1-methylpiperidin-4-yl)amine{(1H-benzimidazol-2-yl)[3-(2-fluorobenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine2-[(1-methylpiperidin-4-yloxy)(2′-methylsulfanylbiphenyl-3-yl)methyl]-1H-benzimidazole2-[(4′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(1-methylpiperidin-4-yloxy)(3′-methylsulfanylbiphenyl-3-yl)methyl]-1H-benzimidazole2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)(4′-trifluoromethylbiphenyl-3-yl)methyl]-1H-benzimidazole{(1H-benzimidazol-2-yl)[3-(tetrahydropyran-2-yloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine2-[(2′-chlorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(3′,4′-dichlorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-2-yl}methanol{(1H-benzimidazol-2-yl)[3-(4-methoxybenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine{(1H-benzimidazol-2-yl)[3-(3-methoxybenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-ylamino)methyl]phenol{3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]biphenyl-2-yl}methanol2-[(1-methylpiperidin-4-yloxy)(3′-methylsulfanylbiphenyl-3-yl)methyl]benzothiazole{(1H-benzimidazol-2-yl)[3-(2-methylbenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine{(1H-benzimidazol-2-yl)[3-(4-methylbenzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-nitrophenyl)methyl](1-methylpiperidin-4-yl)amine[(3-azidophenyl)(1H-benzimidazol-2-yl)methyl](1-methylpiperidin-4-yl)amine2-[(3′,4′-dichlorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole{(1H-benzimidazol-2-yl)[3-(2-ethoxyethoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-pent-4-enyloxyphenyl)methyl](1-methylpiperidin-4-yl)amine2-[(4′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(2′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole{3′-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-4-yl}carbamicacid tert-butyl ester2-[(3′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)(4′-trifluoromethylbiphenyl-3-yl)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)(2′,3′,4′-trifluorobiphenyl-3-yl)methyl]benzothiazole2-[(2′-fluorobiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole{3′-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]biphenyl-4-yl}carbamicacid tert-butyl ester[(1H-benzimidazol-2-yl)(3-furan-2-ylphenyl)methyl](1-methylpiperidin-4-yl)amine[(1H-benzimidazol-2-yl)(3-but-3-enyloxyphenyl)methyl](1-methylpiperidin-4-yl)amine{(1H-benzimidazol-2-yl)[3-(4-methylpentyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine2-[(1-methylpiperidin-4-yloxy)(3-pyrazol-1-ylphenyl)methyl]benzothiazole2-[(3-benzylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole{(1H-benzimidazol-2-yl)[3-(2,5-difluoro-benzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine2-[(3-benzylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(2-chlorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(3-ethylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(3-ethylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}aceticacid methyl ester2-[(3-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2[[3-(2,5-difluorobenzyloxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanol2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanol2-[(3-ethylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}aceticacid methyl ester2[[3-(2,3-difluorobenzyloxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole{(1H-benzimidazol-2-yl)[3-(2,3-difluoro-benzyloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine2[[3-(2-fluoroethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)(m-tolyl)methyl]-1H-benzimidazole5,6-dichloro-2-[(1-methylpiperidin-4-yloxy)phenyl-methyl]-1H-benzimidazole5-fluoro-2-[(1-methylpiperidin-4-yloxy)phenyl-methyl]-1H-benzimidazole2-[(2-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(1-methylpiperidin-4-yloxy)(3-pent-4-enyloxy-phenyl)methyl]benzothiazole2-{(1-methylpiperidin-4-yloxy)[3-(4,4,4-trifluoro-butoxy)phenyl]methyl}benzothiazole5-bromo-2-[(1-methylpiperidin-4-yloxy)phenyl-methyl]-1H-benzimidazole2[[3-(3-fluorobenzyloxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzonitrile2[[3-(furan-2-ylmethylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole((1H-benzimidazol-2-yl)-{3-[3-(2-methyl-[1,3]dioxolan-2-yl)-propoxy]phenyl}methyl)(1-methylpiperidin-4-yl)amine{(1H-benzimidazol-2-yl)[3-(4,4,4-trifluoro-butoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine2[[3-(3-fluoropropoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)-p-tolyl-methyl]-1H-benzimidazole2-{(1-methylpiperidin-4-yloxy)[3-(3,3,3-trifluoro-propoxy)phenyl]methyl}benzothiazole2-[(4-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole{(1H-benzimidazol-2-yl)[3-(2-fluoro-ethoxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine((1H-benzimidazol-2-yl)-{3-[2-(6,6-dimethyl-bicyclo[3.1.1]hept-2-en-2-yl)ethoxy]phenyl}methyl)(1-methylpiperidin-4-yl)amine2-[(1-methylpiperidin-4-yloxy)(4′-trifluoromethoxy-biphenyl-3-yl)methyl]-1H-benzimidazole2-[(4′-methoxybiphenyl-3-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(3-benzo[1,3]dioxol-5-ylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2[[3-(3-methoxybenzyloxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentan-2-one2-{(1-methylpiperidin-4-yloxy)[3-(3-trifluoromethyl-benzyloxy)phenyl]methyl}benzothiazole4-[benzothiazol-2-yl(3-bromo-phenyl)methoxy]-1,1-dimethylpiperidinium2-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)isoindole-1,3-dione3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-yn-1-ol4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-yn-1-ol5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-yn-1-ol2-[(1-methylpiperidin-4-yloxy)-o-tolyl-methyl]-1H-benzimidazole3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynylamine2-[(3-ethynylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-{(1-methylpiperidin-4-yloxy)[3-(3-nitro-benzyloxy)phenyl]methyl}benzothiazole3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]benzonitrile2-{(1-methylpiperidin-4-yloxy)[3-(1H-[1,2,3]triazol-4-yl)phenyl]methyl}-1H-benzimidazole3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]benzoic acidmethyl ester2-[(1-methylpiperidin-4-yloxy)phenyl-methyl]-3H-benzimidazol-4-ylamine2-[(1-methylpiperidin-4-yloxy)(3-methylsulfanyl-phenyl)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)(3-methylsulfanyl-phenyl)methyl]-1H-benzimidazole2-[(3-methanesulfonylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(4-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}acrylicacid tert-butyl ester3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]benzoic acid ethylester{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}methanol3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}propionicacid tert-butyl ester2[[3-(2-benzenesulfonylvinyl)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)phenyl-methyl]-3H-benzimidazol-4-ol[benzothiazol-2-yl(4′-methoxy-biphenyl-3-yl)methyl](1-methylpiperidin-4-yl)amine2[[3-(2-methanesulfonylvinyl)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(2-chloro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrimidin-2-ol2-[(3-tert-butylsulfanylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(1-methylpiperidin-4-yloxy)(3-pyrimidin-5-yl-phenyl)methyl]benzothiazole3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}acrylonitrile2-[(1-methylpiperidin-4-yloxy)(3-vinyl-phenyl)methyl]benzothiazole3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]-N-benzyl-N-methylbenzamide3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]-N-propylbenzamide2-[(2,4-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole[(1H-benzimidazol-2-yl)(4′-methoxy-biphenyl-3-yl)methyl](1-methylpiperidin-4-yl)amine3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]-N-methyl-N-phenylbenzamide3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylamine2-[(3-chlorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(4-chlorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-yn-1-ol3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxymethyl}-phenylamine2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanol2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethanol2-[(3-azidophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-{(1-methylpiperidin-4-yloxy)[3-(2-pyrazin-2-yl-ethylsulfanyl)phenyl]methyl}-1H-benzimidazole2-{(1-methylpiperidin-4-yloxy)[3-(2-pyrazin-2-yl-ethylsulfanyl)phenyl]methyl}benzothiazole{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}benzyl-amine3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-3-methyl-butan-1-ol4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-yn-1-ol5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-yn-1-ol4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}butan-1-ol(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}-cyclopropyl)aceticacid methyl ester2-{(1-methylpiperidin-4-yloxy)[3-(2-[1,2,3]triazol-2-yl-ethylsulfanyl)phenyl]methyl}benzothiazole2-{(1-methylpiperidin-4-yloxy)[3-(2-[1,2,3]triazol-1-yl-ethylsulfanyl)phenyl]methyl}benzothiazole3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-3-methyl-butan-1-ol2-[(1-methylpiperidin-4-yloxy)(3-morpholin-4-yl-phenyl)methyl]benzothiazole2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethanol2-[(1-methylpiperidin-4-yloxy)(3-vinyl-phenyl)methyl]-1H-benzimidazole3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propan-1-ol1-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propan-2-ol4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butan-1-ol2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine2-{(1-methylpiperidin-4-yloxy)[3-(2-methylsulfanyl-ethoxy)phenyl]methyl}benzothiazole2-[(1-methylpiperidin-4-yloxy)(2-trifluoromethoxy-phenyl)methyl]-1H-benzimidazole2-[(1-methylpiperidin-4-yloxy)-p-tolylmethyl]-1H-benzimidazole2-[(1-methylpiperidin-4-yloxy)-p-tolyl-methyl]-1H-benzimidazole3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propan-1-ol1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propan-2-ol4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butan-1-ol2-(1-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}-cyclopropyl)ethanol3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}propan-1-ol2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}-N-methylacetamide2-{(1-methylpiperidin-4-yloxy)[3-(2H-pyrazol-3-yl)phenyl]methyl}benzothiazole2-[(3-bromo-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(2-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetamide{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}aceticacid hydrazide2-{(1-methylpiperidin-4-yloxy)[3-(pyridin-4-ylmethoxy)phenyl]methyl}benzothiazole4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}butan-1-ol2[[3-(furan-2-ylmethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole2-(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}-cyclopropyl)ethanol2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]benzyloxy}propan-2-one2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethylamine2-[(1-methylpyrrolidin-3-yloxy)phenyl-methyl]-1H-benzimidazole[(1H-benzimidazol-2-yl)-p-tolyl-methyl](1-methylpiperidin-4-yl)amine2-[(3-ethylsulfanyl-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole1-(3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyloxy)-propan-2-one1-(3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyloxy)-propan-2-ol2[[3-(2-methoxyethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazoleN-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethyl)methyl-amine2-[(1-methylpiperidin-4-yloxy)(3-trifluoromethoxy-phenyl)methyl]-1H-benzimidazole2-[(2-chlorophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynylamine2-{(1-methylpiperidin-4-yloxy)[3-(pyridin-2-ylmethoxy)phenyl]methyl}benzothiazole2-{(1-methylpiperidin-4-yloxy)[3-(pyridin-3-ylmethoxy)phenyl]methyl}benzothiazole2-[(3-Cyclohexylmethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynylamine5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propane-1,2-diol5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pentylamine2-{3-[benzothiazol-2-yl(1-ethyl-piperidin-4-yloxy)methyl]phenoxy}ethylamine2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethylamine6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}hexan-1-ol4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}butylamine5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}hexan-1-ol3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynylamine2-[benzo[1,3]dioxol-5-yl(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)-urea(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)(4,5-dihydro-thiazol-2-yl)amine2-[(2,3-dihydrobenzo[1,4]dioxin-6-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}butylamineN-(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}propylamineN-tert-butoxycarbonyl-N′-(2-{3-[(benzothiazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}pentylamine2-[{3-[2-(1-methyl-1H-imidazol4-yl)ethyl]phenyl}(1-methylpiperidin-4-yloxy)methyl]benzothiazoleN-tert-butoxycarbonyl-N′-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynyl)guanidineN-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}butyl)guanidineN-tert-butoxycarbonyl-N′-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}butyl)guanidine2-{(1-methylpiperidin-4-yloxy)[3-(pyridin-2-ylmethoxy)phenyl]methyl}-1H-benzimidazole3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}propylamine5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pentylamineN-tert-butoxycarbonyl-N′-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}propyl)guanidine3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propylamine2-{(1-methylpiperidin-4-yloxy)[3-(4-[1,2,3]triazol-2-yl-butoxy)phenyl]methyl}benzothiazole2-{(1-methylpiperidin-4-yloxy)[3-(4-[1,2,4]triazol-1-yl-butoxy)phenyl]methyl}benzothiazole(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)(4,5-dihydro-1H-imidazol-2-yl)amineN-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)-N′-cyanoguanidine6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynylamineN-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}propyl)guanidineN-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}propyl)guanidine2-{(1-methylpiperidin-4-yloxy)[3-(4-morpholin-4-yl-butoxy)phenyl]methyl}benzothiazole(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-2-yl)methanol(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-2-yl)methanol6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}hexylamine4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butylamine3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}propylamine4-(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethyl)piperazine-1-carboxylicacid tert-butyl ester4-(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethyl)piperazine-1-carboxylicacid tert-butyl ester2-{(1-methylpiperidin-4-yloxy)[3-(2-piperazin-1-yl-ethoxy)phenyl]methyl}benzothiazole4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}butylamine2-{(1-methylpiperidin-4-yloxy)[3-(4-morpholin-4-yl-butoxy)phenyl]methyl}-1H-benzimidazole2-{(1-methylpiperidin-4-yloxy)[3-(4-piperidin-1-yl-butoxy)phenyl]methyl}-1H-benzimidazole2-[(2-fluoro-3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazoleN-tert-butoxycarbonyl-N′-(-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pentyl)guanidineN-tert-butoxycarbonyl-N′-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)guanidine6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynylamine2-{(1-methylpiperidin-4-yloxy)[3-(1,2,3,6-tetrahydro-pyridin-4-yl)phenyl]methyl}-1H-benzimidazoleN-tert-butoxycarbonyl-N′-(5-{3-[(benzothiazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-5-ynyl)guanidineN-(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)guanidineN-tert-butoxycarbonyl-N′-(6-{3-[(benzothiazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)guanidineN-(6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)guanidine4-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}butyl)piperazine-1-carboxylicacid tert-butyl ester6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hexylamineN-tert-butoxycarbonyl-N′-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)guanidineN-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)guanidine1-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)-3-isopropyl-thiourea2-{(1-methylpiperidin-4-yloxy)[3-(3-[1,2,4]triazol-1-yl-propoxy)phenyl]methyl}benzothiazole2-{(1-methylpiperidin-4-yloxy)[3-(3-[1,2,3]triazol-2-yl-propoxy)phenyl]methyl}benzothiazole2-{(1-methylpiperidin-4-yloxy)[3-(3-morpholin-4-yl-propoxy)phenyl]methyl}benzothiazole4-(3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}propyl)piperazine-1-carboxylicacid tert-butyl ester2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-phenylsulfanyl}ethylamine4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}-3,6-dihydro-2H-pyridine-1-carboxamidine2[[3-(2-chloroethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazoleN-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hexyl)guanidine2-{(1-methylpiperidin-4-yloxy)[3-(2-piperidin-1-yl-ethoxy)phenyl]methyl}-1H-benzimidazoleN-tert-butoxycarbonyl-N′-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)guanidineN-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)guanidine4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butylamine4-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}propyl)piperazine-1-carboxylicacid tert-butyl ester(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethylamino)aceticacid tert-butyl ester4-(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentyl)piperazine-1-carboxylicacid tert-butyl esterN-(6-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}hexyl)guanidineN-tert-butoxycarbonyl-N′-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hexyl)guanidineN-(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pentyl)guanidine4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}butylamine[[3-(4-aminobutoxy)phenyl](1H-benzimidazol-2-yl)methyl](1-methylpiperidin-4-yl)amine3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propylamine4-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethyl)piperazine-1-carboxylicacid tert-butyl ester(2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}ethylamino)aceticacid tert-butyl ester5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentylamineN-(4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynyl)guanidineN-(3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)guanidineN-(4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}butyl)guanidine(5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentylamino)aceticacid tert-butyl ester2-[(1-methylpiperidin-4-yloxy)(3-piperidin-4-ylethynyl-phenyl)methyl]-1H-benzimidazole2-{(1-methylpiperidin-4-yloxy)[3-(piperidin-4-ylmethoxy)phenyl]methyl}benzothiazole2-{(1-methylpiperidin-4-yloxy)[3-(piperidin-3-ylmethoxy)phenyl]methyl}benzothiazole2[[3-(1-methylpiperidin-3-ylmethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole2-[(1-methylpiperidin-4-yloxy)(3-piperidin-3-ylethynyl-phenyl)methyl]-1H-benzimidazole5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}pentylamine2-{(1-methylpiperidin-4-yloxy)[3-(pyrrolidin-3-yloxy)phenyl]methyl}benzothiazole2-{(1-methylpiperidin-4-yloxy)[3-(pyrrolidin-3-yloxy)phenyl]methyl}benzothiazole5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-en-1-ol3-amino-4-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamino)-cyclobut-3-ene-1,2-dione[[3-(6-aminohex-1-ynyl)phenyl](1H-benzimidazol-2-yl)methyl](1-methylpiperidin-4-yl)amine{[3-(4-aminobutoxy)phenyl]benzothiazol-2-yl-methyl}(1-methylpiperidin-4-yl)amine2-[(3-azetidin-3-ylethynylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-en-1-ol5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-en-1-ol4-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentyl)piperazine-1-carboxylicacid tert-butyl ester2[[3-(2-azetidin-3-ylethyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazoleN-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynyl)guanidine4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}piperidine-1-carboxamidine2-{(1-methylpiperidin-4-yloxy)[3-(2-piperidin-2-yl-ethylsulfanyl)phenyl]methyl}-1H-benzimidazole2-{(1-methylpiperidin-4-yloxy)[3-(2-piperidin-4-yl-ethyl)phenyl]methyl}-1H-benzimidazoleN-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pentyl)guanidine2-[{3-[3-(3H-imidazol-4-yl)propylsulfanyl]phenyl}(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazoleN-tert-butoxycarbonyl-W-(4-{3-[(benzothiazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}but-3-ynyl)guanidine5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentylamineN-acetyl-N′-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine2[[3-(azetidin-3-yloxy)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}azetidin-3-ol(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)methanol1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}piperidin-4-ylamine1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ol1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-olN-(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)acetamide2[[3-(5-imidazol-1-ylpent-1-ynyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-{(1-methylpiperidin-4-yloxy)[3-(5-pyrazol-1-yl-pent-1-ynyl)phenyl]methyl}-1H-benzimidazole1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}piperidin-4-ol2-[{3-[2-(1H-imidazol-4-yl)ethyl]phenyl}(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazoleacetic acid1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}piperidin-4-ylester2-[(3-bromo-phenyl)(1-methyl-pyrrolidin-3-ylmethoxy)methyl]-1H-benzimidazole2-{(1-methylpiperidin-4-yloxy)[3-(piperidin-4-yloxy)phenyl]methyl}benzothiazole2-{(1-methylpiperidin-4-yloxy)[3-(5-[1,2,3]triazol-2-yl-pent-1-ynyl)phenyl]methyl}-1H-benzimidazole2-{(1-methylpiperidin-4-yloxy)[3-(5-[1,2,3]triazol-1-yl-pent-1-ynyl)phenyl]methyl}-1H-benzimidazoleN-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)guanidineN1-(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenoxy}pentyl)butane-1,4-diamine{[3-(6-aminohex-1-ynyl)phenyl]benzothiazol-2-yl-methyl}(1-methylpiperidin-4-yl)amine5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-enylamine4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}but-2-en-1-ol1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ylamine2-[(2,5-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(2-fluoro-5-iodo-phenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylethynyl}azetidine-1-carboxamidine4-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butan-1-ol2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ylamine2[[3-(3-fluoropyrrolidin-1-yl)phenyl](1-methylpiperidin-4-yloxy)methyl]benzothiazole4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}but-2-enylamine2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole(enantiomer A)2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole(enantiomer B)N-(2-aminoethyl)-2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetamideN-(2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)guanidine2-(5-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)isoindole-1,3-dione6-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynylamineoxalate4-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butylamineoxalateN-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}propyl)guanidine,dihydrochloride1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-one,oxalateN-(4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butyl)guanidine,dihydrochloride5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}pentan-1-olN-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)-N-(2,2-dimethylpropionyl)guanidine2-[(1-methylpiperidin-4-yloxy)(4-nitrophenyl)methyl]-1H-benzimidazole2-{(1-methylpiperidin-4-yloxy)[3-(pyridin-3-yloxy)phenyl]methyl}benzothiazole,oxalate2-[(3-bromophenyl)(1-methylpyrrolidin-3-ylmethoxy)methyl]-5-fluoro-1H-benzimidazole,oxalate4-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]aniline4-[(1H-benzimidazol-2-yl)(piperidin-4-yloxy)methyl]aniline,hydrochlorideN-(2-amino-ethyl)-2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}acetamide1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}-3-trifluoromethylpyrrolidin-3-ol,oxalate2-[[3-(4,5-dihydro-1H-imidazol-2-ylmethylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[[3-(4,5-dihydro-1H-imidazol-2-ylmethylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5,6-difluoro-1H-benzimidazole2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1-methyl-1H-benzimidazole,dioxalate2-amino-5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}-1,5-dihydroimidazol-4-one2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5,6,7-trifluoro-1H-benzimidazole1-(2-ethoxyethyl)-2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,dioxalate3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzaldehyde4-{3-[(1H-benzimidazol-2-yl)(1-methylazetidin-3-ylmethoxy)methyl]phenylsulfanyl}butylamine,oxalate2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzoxazole,oxalate{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}methanol.dimethylsulfoxonium ylide of 3-bromophenylacetic acid methyl ester2-[(2-fluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,enantiomer B2-[(2,6-difluoro-3-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazoleethyl(6-{3-[(1-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynyl)carbamate,oxalate2-[(1H-indol-6-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,oxalate2-[benzo[b]thiophen-6-yl(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,oxalate2-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,enantiomer B2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol2-[(1H-benzimidazol-2-yl)hydroxymethyl]phenol2-[(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylimino)phenylmethyl]phenol5-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylimino)-2-methylcyclopent-1-enol2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,enantiomer B5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine,enantiomer A5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamine,enantiomer B2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole,enantiomer A2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole,enantiomer B2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-methylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenolenantiomer A2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenolenantiomer B6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-3-methylphenolenantiomer A6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-3-methylphenolenantiomer B6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2,3-difluorophenolenantiomer A6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2,3-difluorophenolenantiomer B5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}pent-4-ynylamine,dioxalate3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}cyclopentylamine,oxalate2-{[3-(3-fluoropyrrolidin-1-yl)phenyl](1-methylpiperidin-4-yloxy)methyl}benzothiazole,oxalate5-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpyrrolidin-3-ylmethoxy)methyl]phenyl}pent-4-ynylamine,oxalate2-[(3-bromophenyl)(1-methylpyrrolidin-3-ylmethoxy)methyl]benzothiazole,oxalate (one epimer)2-[(3-bromophenyl)(1-methylpyrrolidin-3-ylmethoxy)methyl]benzothiazole,oxalate (50/50 mixture of two epimers)2-{(1-methylpiperidin-4-yloxy)[3-(octahydrocyclopenta[c]pyrrol-5-yloxy)phenyl]methyl}benzothiazole,dioxalate(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)methylamine,dioxalate4-{3-[(5,6-difluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butan-1-ol2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}octahydrocyclopenta[c]pyrrol-5-ylamine,dioxalate2-{[3-(3-fluoropropoxy)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H-benzimidazole,oxalate2-{[3-(2-fluoroethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H-benzimidazole,oxalate4-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}cyclohexylamine,oxalate6-{3-[(1-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynylamine,dioxalate1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-2-ylmethylamine,oxalate(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)(methyl)amine,oxalate(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)(dimethyl)amine,oxalate2-{[3-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2-yl)phenyl](1-methylpiperidin-4-yloxy)methyl}benzothiazole,dioxalate2-[(2-fluoro-5-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,oxalate3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenol,oxalate2-{[2-fluoro-5-(2-fluoroethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H-benzimidazole,oxalate2-[(2-fluoro-5-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,oxalate4-{3-[(1-methylpiperidin-4-yloxy)(5,6,7-trifluoro-1H-benzimidazol-2-yl)methyl]phenylsulfanyl}butylamine,oxalate4-{3-[(5,6-difluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}butylamine,oxalate6-(3-{[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl](1-methylpiperidin-4-yloxy)methyl}phenyl)hex-5-ynylamine,dioxalate6-(3-{[1-(2-methoxyethyl)-1H-benzimidazol-2-yl](1-methylpiperidin-4-yloxy)methyl}phenyl)hex-5-ynylamine,dioxalate2-{[3-(3-fluoropropylsulfanyl)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H-benzimidazole,dioxalate5-fluoro-2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,oxalate4,5,6-trifluoro-2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole5,6-difluoro-2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-{[2-fluoro-5-(2,2,2-trifluoroethoxy)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H-benzimidazole2-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(2-chloro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,oxalate2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole,oxalate2-[(4-chloro-2,6-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole7-fluoro-2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,oxalate2-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole,oxalate2-[(4-chloro-2,6-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole,oxalate2-[(3-ethoxy-2,6-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(2,6-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzoxazole,oxalate2-[(1-methylpiperidin-4-yloxy)(4-trifluoromethylphenyl)methyl]-1H-benzimidazole2-[(2-fluoro-4-trifluoromethylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(2,4-dimethylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(3-methoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[chroman-7-yl(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(2-fluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzoxazole,oxalate2-[(3,5-bis-trifluoromethylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,oxalate5-fluoro-2-[(2-fluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(2,3-difluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(3-chloro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazoleethyl2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzimidazole-1-carboxylate,oxalate2-[(3-fluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(5-bromo-2-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylamine,oxalate5-{4-fluoro-3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynylamineethyl(5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}pent-4-ynyl)carbamate2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-chlorophenolethyl(5-{4-fluoro-3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-ynyl)carbamate2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-trifluoromethoxyphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-methoxyphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-methylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-bromophenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-ethoxyphenol2-[(1H-indol-7-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4,6-difluorophenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4,6-dichlorophenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-3-fluorophenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4,5-difluorophenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-fluorophenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-chlorophenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-methylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-methylsulfanylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-ethylsulfanylphenol3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]biphenyl-4-ol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-tert-butylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-propylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-methoxyphenol2-[(1H-benzimidazol-2-yl)(1-methy-piperidin-4-yloxy)methyl]-3-fluoro-5-methylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-3-chlorophenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluoro-4-ethylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-benzylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-trifluoromethylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-chloro-6-fluorophenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-3-methylphenol6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-3-methylphenol6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]indan-5-ol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-propoxyphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-(1-methyl-1-phenylethyl)phenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-(2-fluoroethoxy)phenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-(3-fluoropropoxy)phenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluoro-6-methylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluoro-4-methoxyphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-phenoxyphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluoro-6-methoxyphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4,5-dimethylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-(3-fluoropropylsulfanyl)phenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluoro-5-methylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-(2-fluoroethylsulfanyl)phenol3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-hydroxybiphenyl2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-ethylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-trifluoromethylphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-hydroxyphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5,6,7,8-tetrahydro-1-naphthol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-trifluoromethoxyphenol2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-5-trifluoromethoxyphenol6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2-fluoro-3,4-dimethylphenol6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-3-fluoro-2-methylphenol6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2,4-difluoro-3-methylphenol6-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-2,3-difluorophenol(1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}-azetidin-3-yl)dimethylamine,oxalate1-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-ol,oxalate2-{(1-methylpiperidin-4-yloxy)[3-(pyrrolidin-3-yloxy)phenyl]methyl}-1H-benzimidazole,dioxalate2-[(5-chloro-2-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,oxalate2-[(2-fluoro-5-trifluoromethylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,oxalate6-{3-[(1-ethyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}hex-5-ynylamine,oxalate2-[(2-fluoro-5-methoxyphenyl)(1-methylpyrrolidin-3-ylmethoxy)methyl]-1H-benzimidazole,oxalate2-[(1-methylpiperidin-4-yloxy)(3-trifluoromethylsulfanylphenyl)methyl]-1H-benzimidazole,oxalate2-[(4-fluoro-3-trifluoromethoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,oxalate2-[(2-fluoro-5-propoxyphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole,oxalate4-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol2-{[3-(3,3-difluoropyrrolidin-1-yl)phenyl](1-methylpiperidin-4-yloxy)methyl}-1H-benzimidazole,dioxalate2-{[3-(5-fluorohexahydrocyclopenta[c]pyrrol-2-yl)phenyl](1-methylpiperidin-4-yloxy)methyl}benzothiazole,dioxalate6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}hexylamine,oxalate5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}oxazolidin-2-oneN-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}hexyl)guanidine,dihydrochloride4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}but-2-enylamine4-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}but-2-enylamine,oxalateN-(2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)-N-isobutyrylguanidine3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}allylaminecis-2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanylmethyl}cyclopropylmethylamineN-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}allyl)guanidine,trihydrochloride2-[(azetidin-3-ylmethoxy)(3-bromophenyl)methyl]-1H-benzimidazole2-[(3-bromophenyl)(1-methylazetidin-3-ylmethoxy)methyl]-1H-benzimidazole2-[(2,6-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(2-fluoro-4-methylphenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(5-ethylsulfanyl-2-fluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(azetidin-3-ylmethoxy)(2-fluoro-5-trifluoromethoxyphenyl)methyl]-1H-benzimidazole,oxalate2-[(2-fluoro-5-trifluoromethoxyphenyl)(1-methylazetidin-3-ylmethoxy)methyl]-1H-benzimidazole,oxalate2-[(3-ethylsulfanyl-2,6-difluorophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(2,2-difluorobenzo[1,3]dioxol-5-yl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole2-[(piperidin-4-yloxy)thiophen-3-ylmethyl]-1H-benzimidazole2-[(1-methylpiperidin-4-yloxy)thiophen-3-ylmethyl]-1H-benzimidazole2-[(piperidin-4-yloxy)thiophen-2-ylmethyl]-1H-benzimidazole2-[(1-methylpiperidin-4-yloxy)thiophen-2-ylmethyl]-1H-benzimidazole aswell as their enantiomers, diastereomers, mixtures thereof andpharmaceutically acceptable salts, free forms, tautomers, hydrates andsolvates.